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Abstract. – OBJECTIVES: Lower respiratory
tract infections (LRTIs), including pneumonia
and acute exacerbations of Chronic Obstructive
Pulmonary Disease (COPD), are among the most
common diagnoses in both outpatient and inpa-
tient settings. Due to the burden of LRTIs health-
care providers must adopt practices focused on
improving outcomes with the aim to reduce
treatment failure and antibiotic resistances.
Moreover, the role of acute and chronic infection
in the pathogenesis of COPD has received con-
siderable attention, since chronic infection can
contribute to airways inflammation and COPD
progression. This review discusses the role of
cefditoren for the treatment of LRTIs, compared
with the definition of “appropriate” of the WHO
as “the cost-effective use of antimicrobials
which maximizes clinical therapeutic effect
while minimizing both drug-related toxicity and
the development of antimicrobial resistance”.
RESULTS AND CONCLUSIONS: Cefditoren ap-
pears to meet the definition of “appropriate” for
the treatment of LRTIs. In fact, this molecule
shows an adequate pharmacokinetic profile
without t he need for any adjustm ent also in
aged patien ts w ith mild renal impairme nt or
mild-to-moderate hepatic dysfunction. The low
drug-drug interaction potential of cefditoren can
be an advantage also in poly-treated patients.
The antimicrobial spectrum of cefditoren in-
cludes both Gram+ and Gram- bacteria, with
high activity against Streptococcus pneumoniae,
including drug-resistant strains, Haemophilus
infuenzae and Moraxella chatarrhalis. Last, re-
cent findings suggested that cefditoren can be a
valid alternative to levofloxacin in outpatients
European Review for Medical and Pharmacological Sciences
The role of cefditoren in the treatment of lower
community-acquired respiratory tract infections
(LRTIs): from bacterial eradication to reduced
lung inflammation and epithelial damage
F. DI MARCO, F. BRAIDO1, P. SANTUS2, N. SCICHILONE3, F. BLASI4
Department of Health Sciences, Respiratory Unit, San Paolo Hospital, University of Milan, Italy
1Respiratory and Allergology Unit, Department of Internal Medicine (DiMI), IRCCS Azienda
Ospedaliera Universitaria San Martino, Genoa, Italy
2Department of Health Sciences, University of Milan, IRCCS Pulmonary Rehabilitation Fondazione
Salvatore Maugeri, Milan, Italy
3Biomedical Department of Specialist and Internal Medicine (Di.Bi.M.I.S.), Respiratory Unit, University
of Palermo, Italy
4Department of Pathophysiology and Transplantation, University of Milan, IRCCS Fondazione Ca
Granda, Milan, Italy
Fabiano Di Marco and Fulvio Braido contributed equally to this article
Corresponding Author: Fulvio Braido, MD; e-mail: fulvio.braido@unige.it 321
with acute exacerbation of COPD; in this setting
a treatment with cefditoren showed to be associ-
ated with a significant reduction of some key in-
flammatory markers involved in epithelial dam-
age, including KL-6 and IL-6.
Key Words:
Cefd it oren , Co mmunity a cq uire d pn eumonia,
Acute exacerbation of chronic obstructive pulmonary
disease, Cephalosporin.
Introduction
Lower respiratory tract infections (LRTIs), in-
cluding pneumonia and acute exacerbations of
chronic obstructive pulmonary disease (COPD),
are one of the most common diagnoses in both
outpatient and inpatient settings, represent the
most common reason for seeking medical atten-
tion, and are the most frequent indication for an-
tibiotic use1.
Due to the burden of LRTIs on morbidity and
mortality, healthcare providers must adopt prac-
tices aimed at improving outcomes, including a
careful use of antibiotics, in order to reduce treat-
ment failure and the onset of antibiotic resis-
tances. Moreover, the role of acute and chronic
infections in the pathogenesis of COPD has re-
cently received considerable attention, with the
potential benefit of decreasing inflammatory bio-
markers in acute exacerbation of COPD.
2014; 18: 321-332
322
This review is aimed at underlying the appro-
priate use of antimicrobials, as defined by the
World Health Organization (WHO) as “the cost-
effective use of antimicrobials which maximizes
clinical therapeutic effect while minimizing both
drug-related toxicity and the development of an-
timicrobial resistance”2; furthermore, this article
updates published data on cefditoren, from mi-
crobiology to clinical efficacy/safety, and dis-
cusses its role in the control of bronchial inflam-
mation in patients with COPD exacerbation3.
The Burden of Acute Exacerbation
of COPD and Community Acquired
Pneumonia (CAP)
LRTIs represent one of the leading infectious
causes of death worldwide and account for sub-
stantial use of healthcare resources4,5. Welte et al6
have recently published a review on the available
evidence which concerns clinical and economic
burden of CAP among adults in Europe. The an-
nual incidence of CAP is around 1.7 cases per
1000 population with a clear age-related in-
crease. The estimated incidence of CAP in Italy
ranges from 0.8/1000/year in patients younger
than 64 years to 4.8 in those older than 64 years.
When looking at the relationship between pa-
tient’s mortality and presence of comorbidity,
COPD and other lung diseases deserve a relevant
role, with CAP being more common in individu-
als who smoke cigarettes and/or have COPD7.
The European Respiratory Society and The
Lung Health Foundation estimated a European
overall cost due to pneumonia to be as high as
10.1 billion euro: 5.5 related to hospitalization,
0.2 to drugs, 4.1 to indirect cost and outpatients
care. From an hospital perspective, the major de-
terminant of costs were the length of hospital
stay and admissions to the intensive care unit,
whereas costs for staff were the major contribu-
tors to direct costs8. Interestingly, a retrospective
study9showed that a shorter length of hospital
stay did not show an increased readmission rate
and post discharge mortality, while mortality was
significantly higher in patients who were not
treated according to current guidelines recom-
mendations10,11.
COPD is one of the most important causes of
morbidity and mortality overall the word with a
prevalence expected to increase rapidly in the
near future12. Patients with COPD typically expe-
rience acute exacerbation, which may result in
hospitalization. The exact definition of acute ex-
acerbation of COPD is an acute worsening of the
patient’s condition from the stable state, which is
sustained and may warrant the patients to seek
for additional treatment13.Among patients with
severe COPD admitted in hospital for an acute
exacerbation of the disease, the in-hospital mor-
tality rate is 10%, rises to 30% in the following
two months and reaches 49% at 2 years5. Most
exacerbations are associated with bronchial in-
fection14-16, a condition that have negative impact
on the quality of life of COPD patients if they are
frequent.
It has been estimated that exacerbations of
chronic bronchitis are caused in 50-80% of cases
by bacterial infections which can respond to an-
tibiotic therapy3. Some Authors17 have demonstrat-
ed that bacterial infection is present in 48.2% of
patients with moderate-severe stable COPD, and
this figure rises to 69.9% during exacerbations,
when the bacterial concentration in the airways
rises. Patients with a history of frequent exacerba-
tions show an increase of inflammation in the up-
per airways, and bacterial concentration represents
a major causal factor for this inflammatory state18.
Chronic bacterial inflammation can, therefore,
contribute to inflammation in COPD patients and
to the progression of disease, as it acts as a direct
inflammatory stimulus18 . The reduction of the
serum concentration of systemic markers of in-
flammation (e.g. IL-6, IL-8, CRP, TNF-alfa) is
correlated with an improvement of symptoms,
clinical conditions and pulmonary function after
exacerbations3, 19. The association between neu-
trophil inflammation, purulent exudate and bacter-
ial exacerbations is well-established and repre-
sents a strong rationale for the use of antibiotic
therapy during COPD exacerbations20.
COPD is a disease that brings significant eco-
nomic and social costs for drugs, diagnostic pro-
cedures, disease follow-up, out-patients manage-
ment, emergency ward, and hospitalizations, with
approximately 80% of the total costs related to
exacerbation management 21,22.
These data illustrate the importance of a cor-
rect antibiotic management of both acute exacer-
bation of COPD and CAP, conditions which are
associated with a significant economic and social
burden, mainly in case of failure of the therapy
that requires hospitalization.
Antibiotic Therapy in the Resistance Era:
the Need for New Molecules
The onset of resistance to antibiotic therapy
by pathogens of the upper airways represents an
emerging issue. Data collected in 2011 by the
F. Di Marco, F. Braido, P. Santus, N. Scichilone, F. Blasi
Figure 1. Bacterial resistance of penicillin-resistant Streptococcus pneumoniae strains in Italy against most commonly-used
antibiotics used for the treatment of respiratory infections (modified from26).
Cefditoren
Cefotaxime
Ceftriaxone
Levofloxacin
Amoxicillin
Amox/clavulanicacid
Clarithromycin
Azithromycin
Cefuroxime
Cefpodoxime
Cefaclor
The role of cefditoren in the treatment of LRTIs
323
teins result in increased minimum inhibitory con-
centration (MIC) values for cefditoren and other
β-lactam agents24,25.
Noteworthy, a recent epidemiological study,
conducted in Italy, has documented the lack of
resistance to cefditoren of penicillin-resistant
strains of Streptococcus pneumoniae, differing
from other cephalosporins, some macrolides and
fluoroquinolones (Figure 1)26.
Pharmacokinetics of Cefditoren
Cefditoren is the active form of cefditoren
pivoxil. After oral administration, the prodrug
cerditoren pivoxil is rapidly and completely hy-
drolyzed by esterases as it passively diffuses
through the intestinal membrane to form cefdi-
toren and pivalate27. In fasting patients, the oral
bioavailability of cefditoren pivoxil ranges from
15% to 20%, but when administered with high-
fat meals, the mean maximum concentration
(Cmax) and area under the concentration-time
curve (AUC) values increases to 50% and 70%,
respectively27. Cmax and AUC values after admin-
istration of Cefditoren pivoxil 400 mg twice dai-
ly for 7 days are similar to those after a single
dose, thus, indicating that accumulation of the
drug does not occur.
Since β–lactam have a time-dependent effica-
cy, it is necessary to maximize the exposure of
European Antimicrobial Resistance Surveillance
Network (EARS-Net) show that in Italy, 5-10%
ofStreptococcus pneumoniae strains are resis-
tant to penicillin, while 30% are resistant to
macrolides23. In this scenario – which can be at-
tributed, at least in part, to a sometimes inap-
propriate use of available antibiotics – it be-
comes interesting to evaluate the recent intro-
duction of cefditoren, an oral, third-generation
cephalosporin: the use of a new antibiotic for the
therapy of respiratory infections can reduce treat-
ment failures and contribute to prevent the spread
of bacterial resistances3.
Cefditoren, an oral cephalosporin with a broad
spectrum of activity against Gram-positive and
Gram-negative bacterial species has structural
components similar to those of first and third-
generation cephalosporins. The group attached at
the C-7 position of the cephem skeleton retains
activity against Gram-negative microorganisms,
whereas the group attached at the C-3 position,
not present in other non-first-generation
cephalosporins, affords activity against Gram-
positive bacteria. Like other β-lactam agents,
cefditoren inhibits the synthesis of cell walls by
binding to penicillin-binding proteins: this bind-
ing results in the loss of cell wall integrity and a
subsequent rapid cellular death. Alterations of
amino acids in significant penicillin-binding pro-
324
bacteria to the molecule by increasing the time
of serum concentrations over MIC (t > MIC),
expressed as percentage of the time interval be-
tween doses. Cephalosporins should have a t >
MIC of 40% to exert a bacteriostatic effect,
while higher t > MIC lead to a bactericidal ef-
fect. In adults, the recommended dose of cefdi-
toren is 400 mg/day (Daily Defined Dose ac-
cording to WHO), in two administrations of 200
mg every 12 hours, in order to increase t > MIC.
At this dose, can exert activity also against sus-
tained infections by S. pneumoniae strains with
intermediate resistance to penicillin (MIC90 =
0.5 mg/L; t > MIC = 54.0%), and a doubling of
daily dose increases t > MIC up to 44.1% (Fig-
ure 2)28,29.
Cefditoren is widely distributed and penetrates
into bronchial mucosa, and epithelial lining fluid.
Between 1 and 4 hours after a single 400 mg
dose of cefditoren pivoxil in patients undergoing
fibre-optic broncoscopy, mean cefditoren con-
cen t rati o n in bron c hial mu c osa (0. 5 6-1.0 4
mg/kg) and epithelial lining fluid (0.30-0.39
mg/L) were therapeutically relevant (tissue-to-
plasma concentration rations at 4 hours were
0.545 and 0.318, respectively) (Figure 3)27.
Both age and gender can affect the pharmacoki-
netics of cefditoren, but these variations are not
considered clinically relevant; thus dose adjust-
ment is not recommended. Only moderate (creati-
nine clearance between 30 and 50 mL/min), or se-
vere (creatinine clearance lower than 30 mL/min)
renal impairment significantly affect its clear-
ance27; thus, dosage adjustment is recommended
in patients with moderate or severe renal impair-
ment. Mild -to-moderate hepatic dysfunction
(Child-Pugh class A or B) does not clinically af-
fect the plasma concentrations of cefditoren and,
therefore, no dosage adjustments are required in
these patients. In patients with severe hepatic im-
pairment, the pharmacokinetic properties of cefdi-
toren have not been studied27.
Cefditoren pivoxil presents an overall favor-
able drug interaction profile, with no evidence in-
dicating that cerditoren pivoxil affects the phar-
macokinetics of co-administered agents. Howev-
er, H2-receptor antagonists and aluminium/mag-
nesium-containing antacid suspension, or other
drugs that increase gastric pH, such as proton
pump inhibitors can reduce the Cmax and AUC of
cefditoren and the concomitant administration of
these drugs is not recommended27.
F. Di Marco, F. Braido, P. Santus, N. Scichilone, F. Blasi
Figure 2. t> MIC of most commonly used oral β-lactams against Streptococcus pneumoniae strains (sensitive = Pen-S; inter-
mediate sensitivity = Pen-I; resistant = Pen-R)28,29.
The pharmacokinetics of cefditoren may provide
some advantages in clinical practice. In fact, the
twice-daily administration is more convenient when
compared with amoxicillin, that requires three ad-
ministrations/day, and is more appropriate from a mi-
crobiological point of view when compared with
once daily administration of other oral cephalosporin
that do not guarantee prolonged time with high
plasma concentration. Moreover, the fact that no
dose variation is needed in patients with mild renal
impairment or mild to moderate hepatic disease,
and the favorable drug interaction profile are to be
taken into consideration, since many patients with
respiratory infections present comorbidities.
Antibacterial Activity of Cefditoren
Cefditoren has a broad spectrum of activity
against Gram-positive and Gram-negative bacte-
ria, including common respiratory pathogens
such as Streptocuccus pneumoniae, Haemophilus
influenzae, Moraxella catarrhalis, Streptococcus
pyogenes, Klebsiella pneumoniae, and methi-
cillin-susceptible strains of Staphylococcus au-
reus (MSSA)28,30. The in vitro activity against
respiratory pathogens frequently isolated in Italy,
compared with other commonly used antibiotics,
is shown in Table I26.
Cefditoren s howed high int rin sic activity
against penicillin-susceptible strains of Strep-
tocuccus pneumoniae, with a MIC90 from ≤0.03
to 0.06 µg/mL; the MIC9 0 values against peni-
cillin-intermediate and penicillin-resistant iso-
lates of Streptocuccus pneumoniae ranged from
0.25 to 0.5 µg/mL, and from 0.5 to 1 µg/mL, re-
spectively. It is noteworthy that MIC values of
cefditoren against penicillin-intermediate and -
resistant strains of Streptocuccus pneumoniae
were lower than those of amoxicillin, cefdinir,
cefprozil, cefuroxime, cefixime, ceftibuten, cef-
podoxime, erythromycin, clarithromycin, and
azithromycin. MIC90 values against penicillin
non-susceptible isolates were one-dilution lower
than that of cefotaxime2 6,31-3 8. Antibiotic resis-
tance for Streptocuccus pneumoniae depends on
geographic location and time, antibiotic con-
sumption, and the use of vaccines. Tempera et
al26 found that cefditoren was the only antibiotic
with activity against 100% of the strains of Strep-
tococcus pneumoniae examined, followed by the
third-generation injectable cephalosporins (cefo-
taxime and ceftriaxone), that showed 2% of re-
sistance against penicillin-resistant isolates.
Overall, cefditoren has demonstrated a high
intrinsic activity against Haemophilus influen-
325
The role of cefditoren in the treatment of LRTIs
Figure 3. Diffusion of Cefditoren in respiratory tissues (modified from27). ELF: epithelial lining fluid.
Diffusion of Cefditoren in respiratory tissues
Cefditoren mean concentration
(mg/l or mg/kg)
PlasmaBronchial
mucosaELF
Between 1 and 2 hours
Between 2 and 3 hours
Between 3 and 4 hours
3
2.5
2
1.5
1
0.5
0
326
zae and Streptococcus pyogenes, with an MIC90
≤0.06 µg/mL in the studies performed26,31,33,38-45.
For Haemophilus influenzae,β-lactams resis-
tance is defined by using ampicillin as a marker
of resistance, with most ampicillin-resistant
is olates th at pr oduce β-la ctamase ( TEM -1,
TEM-2, and ROB-1). Another way to develop
resistance against ampicillin is the mutation in
the FTSL gene that causes an alteration in the
amino acid sequences of penicillin-binding pro-
tein 3 (PBP3). The Haemophilus influenzae
phenotypes that show mutations in the FTSL
gene can be identified as β-lactamase negative
ampicillin resistant (BLNAR) or β-lactamase
positive amoxicillin/clavulanic acid resistant
(BLPACR) in case of the concomitant presence
the β-lactamase production other than the FTSL
gene mutation.
In the study of Tempera et al26, cefditoren
was the oral cephalosporin with the highest in
vitro activity against Haemophilus influenzae,
independently of their production of beta-lacta-
mases or their ampicillin resistance. The activi-
ty was c omparable to th at of the inje ctable
cephalosporins and levofloxacin, whereas the
highest MIC90 were found for macrolides (MIC90
values between 4 and 16 mg/L), and cefaclor
(MIC90 values between 4 and 32 mg/L).
In general, Streptococcus pyogenes is to be
considered as highly susceptible to penicillin,
since strains with MIC > 0.12 µg/mL have not
been identified to date. By contrast, resistance to
erythromycin is widely reported; moreover, since
both the mechanisms of resistance found (M-ef-
flux and MLSB) imply resistance to 14- and 15-
membered macrolides, erythromycin resistance
implies resistance to azithromycin and clar-
ithromycin46 . As previously stated, cefditoren
showed high intrinsic activity against Streptococ-
cus pyogenes; in the study of Tempera et al26, all
the 225 strains of Streptococcus pyogenes were
sensitive to cefditoren.
F. Di Marco, F. Braido, P. Santus, N. Scichilone, F. Blasi
Table I. In vitro activity of cefditoren against some respiratory pathogens: comparison of MIC90 with other antimicrobial
agents commonly used) (modified from26).
Data are expressed as MIC90 values (mg/L). PRSP: penicillin-resistant S. pneumoniae; Hiβ+:H. influenzae β-lactamase positive;
Mcβ+:M. cattarhalis β-lactamase positive; S pyo: S. pyogenes; MSSA: methicillin-susceptible S. aureus; Kl pn: K. pneumoniae;
amoxi-clav: amoxicillin-clavulanate.
With respect to penicillin-nonsusceptible (MIC
> 0.12 pg/mL) strains of Streptococcus pneumoni-
ae, cefditoren was associated with a response rate
of 92.3%. When only penicillin-resistant (MIC > 2
pg/mL) strains were considered, the overall re-
sponse rate was 94.4%47.
Clinical Efficacy of Cefditoren in the
Treatment of Lower Community-Acquired
Respiratory Tract Infections
Clinical studies conducted to date have docu-
mented the efficacy of cefditoren in the treatment
of LRTIs, such as exacerbations of chronic bron-
chitis and mild-to-moderate CAP.
The most recent study3enrolled 40 outpatients
with mild to moderate acute exacerbation of
COPD and investigated the effect of cefditoren
(200 mg twice daily for 5 days) and the compara-
tor (levofloxacin 500 mg od for 7 days) on serum
inflammatory biomarkers, further to clinical effi-
cacy and microbiological eradication. Interesting-
ly, the Authors found that the use of cefditoren is
associated with a significant reduction of IL-6 and
KL-6, two mediators of lung inflammation and ep-
ithelial damage. KL-6 decreased both in the over-
all study population (from 19±11 UI/mL to 6±8
UI/mL, p= 0.000) and in the cefditoren (from
19±13 UI/mL to 8±10 UI/mL, p= 0.006) and lev-
ofloxacin (from 19±10 UI/mL to 5±5 UI/mL, p=
0.000) arms. Similarly, IL-6 decreased both in the
overall study popul ation (from 13.35±16.41
pg/mL to 3.0±4.7 pg/mL, p= 0.000) and in the
cefditoren (from 15.90±19.54 pg/mL to 4.13±6.42
pg /mL, p= 0 .015 ) and levo flox acin ( from
10.80±12.55 pg/mL to 1.87±1.16 pg/mL, p=
0.003) arms (Figure 4). At the end of treatment
(test-of-cure, 6-9 days after drug initiation), the
clinical success rate in the overall study popula-
tion was 78%; the clinical cure rate was 80% in
the cefditoren arm and 75% in the levofloxacin
arm (Figure 5). Globally, bacteriological eradica-
tion at test-of-cure was obtained in 85% of the
overall study population. Both treatments were
well tolerated. Thus, Authors concluded that cefdi-
toren represents a valid option in the treatment of
severe cases of acute exacerbation of COPD in the
outpatient care setting3. This work also confirms
the conclusion of a previous probability model
(therapeutic outcomes model) analysis of Canut et
al48, aimed at predicting the likelihood of clinical
success with particular antimicrobial agents in the
treatment of patients with acute exacerbation of
COPD. According to this model, fluoroquinolones
(levofloxacin, ciprofloxacin and moxifloxacin),
cefditoren and amoxicillin/clavulanate are the
most appropriate antibiotics for the treatment of
patients with acute exacerbation of COPD, in
terms of predicted clinical efficacy, with wide dif-
ferences from other antibiotics commonly used in
the treatment of these patients, such as clar-
ithromycin and azithromycin48.
The Benefit of Decreasing Inflammatory
Biomarkers in Acute Exacerbation of COPD
In COPD patients, the innate lung defense is
disrupted as a result of exposure to smoke and
other environmental irritants, with the presence
of two distinct infection cycles (i.e. acute and
chronic; Figure 6) that could contribute to pro-
gressive loss of lung function, leading to the par-
327
The role of cefditoren in the treatment of LRTIs
Figure 4. Levels of KL6 (A) and IL6 (B) with cefditoren and levofloxacin, at visit 1 and test of cure3. *p< 0.05 versus visit
(modified from27).
Variation of serum concentration of
IL-6 before and after treatment
Variation of serum concentrations of
KL-6 before and after treatment
A B
328
adi g m o f “infe c t ion as a com o rbidit y o f
COPD”18. Chronic microbial infection can con-
tribute to inflammation in COPD as a direct in-
flammatory stimulus or indirectly by altering the
host response to tobacco smoke, with COPD pro-
gression significantly affected by the vicious cir-
cle between infection and inflammation18.
Thus, in COPD high level of inflammatory bio-
markers, such as for IL-6 and fibrinogen, are pre-
sent also when patients are in stable condition,
with a further increase during exacerbation. The
increase of inflammatory biomarkers have been
shown to be associated with impaired functional
capacity, reduced daily physical activity, and de-
creased health status49. Notably, two recent reports
in COPD patients demonstrated that high levels of
IL6, but not other biomarkers such as tumor
necrosis factor alpha or IL-8, are predictors of in-
creased mortality and poor clinical outcomes50,51.
Last, KL-6, a biomarker currently largely used for
management of interstitial lung disease, is in-
creased in the lung, induced sputum and plasma of
aged smoking patients, and has been used to as-
sess the presence of fibrosis in the lungs of pa-
tients with combined pulmonary fibrosis and em-
physema52,53. Bacterial load itself is an important
determinant of airway inflammation, with increas-
ing concentrations associated with greater intensi-
ty of neutrophilic airway inflammation14.
Blasi et al3showed that cefditoren in acute ex-
acerbation of COPD is effective in decreasing in-
flammatory biomarkers, such as KL-6, and IL-6,
an effect which is probably related to its antibac-
terial efficacy. The demonstration of a significant
reduction of inflammatory biomarkers after an
appropriate antimicrobial treatment appears clini-
cally significant, especially in a disease charac-
terized by a high level of local and systemic in-
flammation such as COPD.
F. Di Marco, F. Braido, P. Santus, N. Scichilone, F. Blasi
Figure 5. Clinical cure in patients with COPD exacerbation
treated with cefditoren (200 mg twice daily for 5 days) or lev-
ofloxacin (500 mg once daily for 7 days) (modified from27).
Figure 6. A modification in bacterial strains and/or an increase in bacterial load can enhance inflammation in the airways and
elicit COPD exacerbations (modified from18).
Tolerability Considerations
Safety data from the trials carried out in adults
during the clinical development of cefditoren for
the treatment of community-acquired respiratory
infections showed that the tolerability profile of
cefditoren and comparators are similar54.
The tolerability profile of cefditoren pivoxil,
administered either at a dose of 200 or 400 mg
twice daily for up to 14 days has been assessed in
about 6000 patients enrolled in controlled clini-
cal trials. The molecule was overall well-tolerat-
ed: in the wide majority of cases, adverse effects
were of mild-to-moderate severity and sponta-
neously resolved. No deaths or permanent dis-
abilities were correlated with cefditoren pivoxil.
The treatment was interrupted for adverse reac-
tions in 2.6% of patients only54.
β-lactams and fluoroquinolones represent the
more effective drugs for the treatment of patients
with exacerbations of COPD. However, in mild
COPD without comorbidities, oral cephalosporins
should be considered as first-line treatments, while
the use of fluoroquinolones should be reserved for
mo re sever e exa cerb atio ns. In fact , fluo ro-
quinolones, one of the most common alternatives
to β-lactams for the treatment of respiratory infec-
tions, are generally well-tolerated but can be asso-
ciated with adverse drug reactions – potentially se-
vere – which include central nervous system toxic-
ity, phototoxicity, cardiotoxicity, arthropathy, and
tendon toxicity, especially in patients with predis-
posing factors, such as diabetes and heart
disease55. These data have been confirmed in the
analysis of four regional pharmacovigilance data-
bases in Italy56,57. Moreover, because of physiolog-
ical changes in renal function and the high number
of expected comorbidities, some special consider-
ations are needed in elderly patients treated with
fluoroquinolones57,58.
Conclusions
The appropriate use of antimicrobials is defined
by the World Health Organization as “the cost-ef-
fective use of antimicrobials which maximizes
clinical and therapeutic effect while minimizing
both drug-related toxicity and the development of
antimicrobial resistance”2, mainly in an era char-
acterized by a limited number of new antibiotics
in the pipeline. In this context, cefditoren appears
to meet the definition of “appropriate” for the
treatment of LTRIs. In fact, it shows an adequate
pharmacokinetics, with a clinical relevant concen-
tration both in bronchial mucosa and in epithelial
lining fluid after oral administration. Since dosage
adjustment is not needed in aged patients even if
in presence of mild renal impairment or mild to
moderate hepatic dysfunction, cefditoren can be
used in the majority of cases. In patients with
many comorbidities, like most COPD patients, the
low drug-interaction of cefditoren can be a relevant
advantage in the clinical practice. The antimicro-
bial activity of cefditoren answers to the request of
new antibiotics aiming at treating community res-
piratory infections, due to its activity against both
Streptococcus pneumoniae and Haemophilus in-
fluenzae, the most prevalent isolates.
Cefditoren is more expensive than many other
β-lactams and quinolones, including lev-
ofloxacin, at least in Italy, and so far, to the best
of our knowledge, a formal study aimed at evalu-
ating the cost effectiveness of this antibiotic for
the treatment of LTRIs compared with other ones
has not yet been carried out. However, it must be
noted that pharmacoeconomic studies showed
that the cost of the antibiotic itself, although im-
portant, does not play a critical role in the health-
care cost savings for the treatment of respiratory
infections, including CAP and acute exacerbation
of COPD. On the contrary, the choice of antibiot-
ic should be based on spectrum of activity, effica-
cy, dosage regimen and appropriateness for the
infectious episode and each single patient55. In
fact, the cost of the initial antibiotic accounts for
18% only of the total cost in outpatients, and can
be further reduced to 10% in patients who re-
quire hospitalization59. It is noteworthy that in
case of therapeutic failure, a significant increase
of the costs is expected, not only for CAP but al-
so for acute exacerbation of COPD, as demon-
strated by Miravitlles et al60.
Acute exacerbations of COPD and CAP are
usually treated with oral antibiotics since they are
more easily administered and accepted on the part
of the patients. In this field, cefditoren, thanks to
its good pharmacokinetic and pharmacodynamic
profile, may be not only the first choice, but also
the logical option for sequential therapy after
treatment with parenteral cephalosporins, such as
ceftriaxone or cefotaxime. Finally, recent data
have shown that cefditoren represents a valid alter-
native to levofloxacin in the treatment of mild-to-
moderately severe cases of acute exacerbation of
COPD in the outpatients setting, with a significant
reduction of key mediators of lung inflammation
and epithelial damage, factors probably involved
in the progression of the disease.
329
The role of cefditoren in the treatment of LRTIs
330
–––––––––––––––––
Financial support
This review was supported by an unrestricted grant from
Zambon (Italy).
–––––––––––––––––-––––
Conflict of Interest
Fabiano Di Marco has received financial support for re-
search from Novartis, Pfizer and Boehringer Ingelheim. He
has received honoraria for lectures at national meetings
from Chiesi Farmaceutici, Novartis, Zambon, AstraZeneca,
Glax o S mi th Kline , M en ar in i, A lmiral, G ui do tt i, and
Malesci. He is consultant in the field of educational pro-
grams f or Novartis. The auth or states t hat no fundin g
sources influenced the preparation of the current manu-
script in its parts: collection, interpretation and presentation
of data. Pierachille Santus has received financial support
for resea rc h an d for congress at te ndance from Pfizer,
Boehringer Ingelheim, Novartis, Chiesi Farmaceutici,
Glaxo Smith Kline, Menarini, AirLiquide. He has received
honoraria for lectures at national meetings from Chiesi Far-
maceutici, Novartis, Zambon, AstraZeneca. He has served
as consultant for Zambon, Astra Zeneca, Novartis, Chiesi.
The author states that no funding sources influenced the
preparation of the current manuscript in its parts: collec-
tion, interpretation and presentation of data. Fulvio Braido
has received financial support for research and for congress
attendance from Astra Zeneca, GSK, Novartis, Menarini,
Chies, Boheringer, Pfizer, MSD. He has received honoraria
for lectures at national meetings from Astra Zeneca, GSK,
Novartis, Menarini, Chiesi, Zambon, Abbott, Boheringer,
Pfizer, MSD. The author states that no funding sources in-
fluenced the preparation of the current manuscript in its
parts: collection, interpretation and presentation of data.
Nicola Scichilone has received financial support for re-
search and for congress attendance from Boehringer Ingel-
heim, Novartis, Chiesi Farmaceutici, Glaxo Smith Kline,
Menarini. He has received honoraria for lectures at national
meetings from Chiesi Farmaceutici, Novartis, Zambon, Has
served as consultant for Zambon, Astra Zeneca,
Mundipharma, Novartis, Chiesi. The author states that no
funding sources influenced the preparation of the current
manuscript in its parts: collection, interpretation and pre-
sentation of data. Francesco Blasi has received financial
support for research from Pfizer, Novartis, Chiesi, Zambon.
He has received honoraria for lectures at national meetings
from Almi ra ll , Ch ie si , Glaxo Smith Kline, Me na ri ni ,
Guidotti-Malesci, Novartis, Zambon, AstraZeneca. He has
served as consultant for Nova rt is , Ch ie si , Pfizer, As -
traZeneca. The author states that no funding sources influ-
enced the preparation of the current manuscript in its parts:
collection, interpretation and presentation of data.
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