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In vitro antimicrobial activity of cefditoren and otheroral antibiotics against Streptococcus pneumoniae,
isolated from children with community acquired
respiratory tract infections
JIN HAN KANG*, SOO YOUNG LEE, JONG HYUN KIM,
JAE KYUN HUR and KYUNG YIL LEE
Department of Pediatrics, The Catholic University of Korea, Seoul, Korea(Received for publication July 21, 2009)

The antibacterial susceptibility to frequently prescribed antibiotics of Streptococcus
pneumoniae isolated from the pediatric patients with acute respiratory infectious diseases was investigated in a study of three medical institutions in Korea. Total 143 clinical isolates of S. pneumoniae were available for susceptibility tests between May 2003
and July 2007. Antimicrobial susceptibility data for S. pneumoniae were analyzed byusing agents of amoxicillin, cefaclor, cefuroxime, cefdinir, and cefditoren as the test
antibiotics.
The prevalence of each resistance class, penicillin-resistant S. pneumoniae (PRSP)
were high with the proportion of MIC range (susceptible⫽8.4%, intermediate
resistance⫽18.2%, resistance⫽73.4%). MIC90 and susceptible (S) rate of antimicrobial
agents to the strains tested were amoxicillin (MIC90⫽4 m g/ml, S⫽76.2%), cefaclor(MIC90⫽128 m g/ml, S⫽8.4%), cefuroxime (MIC90⫽16 m g/ml, S⫽24.5%), cefdinir(MIC90⫽16 m g/ml, S⫽21.8%), and cefditoren (MIC90⫽0.5 m g/ml, S⫽90.2%) respectively.
Against clinical isolates including PRSP, cefditoren demonstrated the strongest antibacterial activity intrinsically among the antibiotics tested. Conclusively, the antimicrobial activity of cefditoren to S. pneumoniae strains isolated from pediatric patientswith acute respiratory infection is very high. In South Korea, where the antibiotic
resistance of S. pneumoniae is issued, cefditoren is expected to be used as a primary or
secondary antibiotic. Moreover, cefditoren may serve as a useful option for secondary
antibiotics after failure of amoxicillin treatment, which is most primarily used for
acute respiratory S. pneumoniae infection in children.

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S. pneumoniae is widely accepted as one of the most important and common pathogen for bacterial respiratory infection and central nervous system infection. Since PRSP was reported in 1960s,
epidemic multidrug-resistant S. pneumoniae was reported in 19771), and recently multidrug-resistance of PRSP is gradually increasing. Especially, the prevalence of PRSP is very high, more than
55%, in Far Eastern Asia including Hong Kong, Taiwan, South Korea and Japan with high multidrug-resistance2). Furthermore, severe infection caused by highly resistant bacteria has been clinically issued, which requires very special care in choosing antibiotics.
The prevalence of PRSP in South Korea has abruptly increased since the year of 2000, and has
become the highest in the world, unfortunately3). Thus, epidemiological and antibiotic susceptibility-related researches of this bacterium have been widely and aggressively conducted. This bacterium is clinically characterized by more frequent infection in upper and lower respiratory tract andcentral nervous system in children with 5 years or less of age4). As the antibiotic resistance rate is
generally higher in children than adults in the countries with higher prevalence of antibiotic resistant
S. pneumoniae5), basic epidemiological research should be accomplished to investigate the prevalence of this bacteria in nasal cavity and the penicillin resistance rate in young children. Experiencebased treatment is generally provided for outpatients or patients with acute respiratory infection
without complications. In this case, evidence-oriented antibiotic treatment is required based on therepetitive researches of exact resistance patterns about region-speciﬁc causative pathogens for respiratory infection6). Therefore, it is essential to perform region-speciﬁc overall antibacterial assessment of S. pneumoniae, which is the most common and important pathogen for acute bacterial respiratory infections in young children. It is also important to investigate the antibacterial activities oforal antibiotics frequently used for pneumococcal respiratory infections. These investigations maylead to the appropriate use of right antibiotics for S. pneumoniae, and thus ultimately reduced antibiotic resistance.
The objective of this study was to evaluate the PRSP isolated from the patients with acute otitis
media, acute sinusitis and pneumonia in Korean children, and to evaluate the antibacterial activities
of frequently prescribed oral antibiotics which are available in Korea for the community acquired
pneumococcal infections. Five oral antibiotics for pediatric use in Korea were selected for the test;
amoxicillin, the most frequently prescribed aminopenicillin for children, cefaclor and cefuroxime,
the frequently prescribed agents of the ﬁrst- and second-generation oral cephalosporins, and cefdinirand cefditoren, the representative agents of the third-generation oral cephalosporins to evaluate theantibacterial potentiality of the third-generation agents against the clinical isolates among antibiotics
tested.
Total 143 specimens of S. pneumoniae were isolated and analyzed from the patients with community acquired respiratory infections including acute otitis media, acute sinusitis or pneumonia, who
visited Seoul St. Mary’s Hospital, Incheon St. Mary’s Hospital, and St. Vincent’s Hospital from May
2003 to July 2007.

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13 ( 13 )For acute otitis media patients, specimens were readily collected in the case of natural perforation,or collected after paracentesis of ear drum, if indicated and applicable. For acute sinusitis patients,
specimens were collected and incubated by calcium alginate swabs (Fisher Scientiﬁc Co., Georgia,
USA) from the oriﬁce of middle meatus, or paracentesis of sinuses. For pneumonia patients, S.
pneumoniae specimens were isolated from inpatients only, following blood or sputum culture. Theisolates were aliquoted into microplates in Mueller-Hinton broth (MHB, BBL, Cat. No. 431138,USA) with 5% lysed horse blood, and stored at ⫺70°C before use.
The minimal inhibitory concentration (MIC) was determined by broth dilution method in accordance with the criteria of Clinical and Laboratory Standards Institute (CLSI). After determination ofMIC50 and MIC90, the susceptibility range was established according to the standards for antimicrobial susceptibility testing of CLSI 20077). There is no CLSI standard of antimicrobial susceptibilityor resistance for cefditoren, however, this agent was evaluated based on the standard of the Spanish
Drug Agency8).
As the results, the antimicrobial concentration of penicillin against S. pneumoniae ranged from0.015 m g/ml to 16 m g/ml with 8.4% of susceptibility, 91.6% of resistance rate (intermediateresistance: 18.2%, resistance: 73.4%), 4 m g/ml of MIC50 and 8 m g/ml of MIC90 (Table 1). Amoxicillin showed 76.2% of the susceptibility of the study bacteria and 23.8% of resistance rate (intermediate resistance: 18.2%, resistance: 5.6%) with 1 m g/ml of MIC50 and 4 m g/ml of MIC90, suggesting
substantially higher antibacterial potency than penicillin. However, the susceptibility of S. pneumoniae to cefaclor was 8.4% with 91.6% of resistance rate (intermediate resistance: 5.6%, high resistance: 86.0%), which suggests very low antibacterial potency similar to that of penicillin. Furthermore, cefaclor showed signiﬁcantly low intrinsic activities with 64 m g/ml of MIC50 and 128 m g/ml ofMIC90. Cefuroxime showed 24.5% of the susceptibility of the study bacteria and 75.5% of resistance
rate (intermediate resistance: 13.3%, resistance: 62.2%) with 4 m g/ml of MIC50 and 16 m g/ml ofMIC90. Similarly, cefdinir displayed 21.8% of susceptibility and 78.2% of resistance rate (intermediate resistance: 1.3%, resistance 76.9%) with 4 m g/ml of MIC50 and 16 m g/ml of MIC90. However,cefditoren showed 90.2% of susceptibility and 9.8% of resistance rate (intermediate resistance:8.4%, resistance: 1.4%) suggesting the highest susceptibility. Moreover, it also displayed the greatest intrinsic activity with 0.5 m g/ml of MIC50 and 0.5 m g/ml of MIC90 (Table 1).
In this study, we found that pneumococcal susceptibility to cefaclor, cefuroxime and cefdinir wasvery high level of resistant proportion with 62⬃86%, while amoxicillin and cefditoren, in particular,
showed substantially low rate (5.6% and 1.4%, respectively) of resistant proportion.
In South Korea, LEE et al. reported the results of antibacterial activity assessment about
cephalosporins in 2005, where MIC range of cefditoren was 0.125⬃1 m g/ml with 0.5 m g/ml and
1 m g/ml of MIC50 and MIC90, while MIC50 and MIC90 of cefdinir, cefprozil, and cefpodoxime were
4 m g/ml and 8 m g/ml, 8 m g/ml and 16 m g/ml, and 64 m g/ml and 128 m g/ml, respectively, which suggests cefditoren is superior to any other cephalosporins9). In this study, we conducted cefditoren sus-

Table 1. Susceptibility of 143 clinical isolated S. pneumoniae from children.

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15 ( 15 )ceptibility assay against S. pneumoniae isolated from 143 pediatric patients with acute respiratory
infection. The result showed that MIC50 and MIC90 were almost similar with that of LEE et al. in
2005. Subculture study also showed that cefditoren is associated with lower occurrence of mutant
strains with intrinsic resistance10). Persistence of the present antimicrobial activities of cefditoren is
expected from this study forward.
Recently, it was also reported that cefditoren shows antibacterial activities even to penicillin-or
ampicillin-resistant strains, and it exerts the highest antimicrobial activity to S. pneumoniae11,12).
However, there is no established consensus about the standard for susceptibility of cefditoren. FUCHSet al. suggested less than 0.25 m g/ml of MIC for susceptibility standard of cefditoren to S. pneumoniae, 0.5⬃1 m g/ml of MIC for intermediate resistance, and more than 2 m g/ml of MIC for high resistance13), while JONES et al. suggested 0.5⬃1 m g/ml of MIC for susceptibility standard14). In addition, Japanese Chemotherapy Committee applied 1 m g/ml of MIC for susceptibility standard ofcefditoren to S. pneumoniae15), and the Spanish Drug Agency determined less than 0.5 m g/ml ofMIC as susceptibility standard, 1 m g/ml of MIC as intermediate resistance, and more than 2 m g/ml
as high resistance8). This study was conducted based on the standard provided by the Spanish DrugAgency8). As this issue limits the potential signiﬁcance of this study about the comparisonof susceptibility and antimicrobial activity, re-evaluation might be required based on the establishedstandard in future. And, treatment effects need to be continuously further investigated in clinicalpractice.
In conclusion, we investigated in vitro susceptibility of S. pneumoniae strains isolated from pediatric acute respiratory infection patients and found that the antimicrobacterial activity of cefditoren
to S. pneumoniae is so high. In South Korea, where the antibiotic resistance of S. pneumoniae isissued, cefditoren is expected to be used as a primary or secondary antibiotic. Furthermore, cefditoren may serve as a useful option for secondary antibiotics after failure of amoxicillin treatment,
which is most primarily used for acute respiratory S. pneumoniae infection in Korean children.

References
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2) SOH, S. W.; C. L. POH & R. V. T. PIN LIN: Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates from pediatric patients in Singapore. Antimicrob. Agents Chemother.
44: 2193⬃2196, 2000
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pneumococcal pathogens in Asian Countries: Asian network for surveillance of resistant pathogens(ANSORP) study. Infect. Chemother. 35: 298⬃305, 2003
4) LEE, J. A.; N. H. KIM, D. H. KIM, et al.: Serotypes and penicillin susceptibility of Streptococcus
pneumoniae isolated from clinical specimens and healthy carriers of Korean children. J. Korean Pediatr. Soc. 46: 846⬃853, 2003
5) CHARPENTIER, E. & E. TUOMANEN: Mechanisms of antibiotic resistance and tolerance in Streptococcus

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pneumoniae. Microb. Infect. 2 :1855⬃1864, 2000
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韓国における小児市中急性呼吸器感染症から分離した肺炎球菌に対するセフジトレンおよびその他の経口抗生物質の抗菌力
JIN HAN KANG* · SOO YOUNG LEE · JONG HYUN KIM ·JAE KYUN HUR · KYUNG YIL LEE
Department of Pediatrics, The Catholic University of Korea, Seoul, Korea
韓国小児の急性呼吸器感染症から分離された Streptococcus pneumoniae に対して，韓国で繁用されている経口抗生物質の抗菌力を測定した。2003 年 5 月から 2007 年 7 月の間に韓国内 3 医療施設から 143 株の S. pneumoniae を臨床分離して被験菌株とし，抗生物質 amoxicillin, cefaclor,cefuroxime, cefdinir, cefditoren の抗菌活性を調査検討した。分離した S. pneumoniae のペニシリン

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耐性率は高く MIC レンジは (susceptible⫽8.4%, intermediate resistance⫽18.2%, resistance⫽73.4%)であった。そしてその菌株に対する試験薬の MIC90 値と susceptible (S) 比率は，amoxicillin(MIC90⫽4 m g/ml, S⫽76.2%), cefaclor (MIC90⫽128 m g/ml, S⫽8.4%), cefuroxime (MIC90⫽16 m g/ml,S⫽24.5%), cefdinir (MIC90⫽16 m g/ml, S⫽21.8%), cefditoren (MIC90⫽0.5 m g/ml, S⫽90.2%) であった。
ペニシリン耐性株を含む臨床分離 S. pneumoniae に対して cefditoren は試験薬剤の中，単独で最も強い抗菌力を示した。結果として小児の急性呼吸器感染症における S. pneumoniae に対して cefditoren の抗菌薬有用性はもっとも高いものであると示唆される。S. pneumoniae の抗菌薬耐性化が問題となっている韓国において，cefditoren は第一選択もしくは第二選択の抗菌薬として有用性が期待できる。また小児の急性呼吸器感染症で最も多く使われている抗菌薬 amoxicillinが無効の場合には，cefditoren が最も有用な抗菌薬になると考えられた。