Antimicrobial activities of cefditoren against respiratory pathogens isolated from children in Japan

J16Infect Chemother (1999) 5:16–20

© Japan and Society of Chemotherapy 1999 N. Matsuda et al.: EGF receptor osteoblastic differentiation

ORIGINAL ARTICLE Hidetoshi Seki · Yoshihito Kasahara · Kunio Ohta Kazuhide Ohta · Yutaka Saikawa · Ryou Sumita Akihiro Yachie · Shin-ichi Fujita · Shoichi Koizumi

Antimicrobial activities of cefditoren against respiratory pathogens isolated from children in Japan

Received: June 11, 1998 / Accepted: September 7, 1998

Abstract There is an increasing spread and incidence of penicillinresistant bacteria that are becoming less susceptible to commonly prescribed oral antimicrobials, including extended-spectrum cephalosporins. Against this background, we undertook this study to determine the prevalence of penicillin resistance in Streptococcus pneumoniae and the in-vitro activity of oral antimitrobials. Between April 1996 and December 1997, in 245 children with respiratory tract infections (bronchitis in 61, pharyngitis in 115, and tonsillitis in 69), 119 strains of Haemophilus influenzae, 89 strains of Streptococcus pyogenes, 61 strains of Streptococcus pneumoniae, 36 strains of Staphylococcus aureus, and 34 strains of Moraxella catarrhalis were isolated from the pharynx. The antimicrobial susceptibility of these isolates was assessed by a broth microdilution method. The isolation incidence of penicillinintermediately resistant S. pneumoniae (PISP) and penicillin-highly resistant S. pneumoniae (PRSP) was 59.0% and 13.1%, respectively. Most strains of PISP and PRSP

H. Seki (*) Department of Nursing, School of Health Sciences, Faculty of Medicine, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan Tel. 181-76-265-2314; Fax 181-76-262-1866. e-mail: [email protected] Y. Kasahara · K. Ohta · K. Ohta · Y. Saikawa · R. Sumita · S. Koizumi Department of Pediatrics, Kanazawa University, Faculty of Medicine, Kanazawa, Japan A. Yachie Department of Laboratory Science, Kanazawa University, Faculty of Medicine, Kanazawa, Japan S. Fujita Department of Clinical Laboratory, Kanazawa University, Faculty of Medicine, Kanazawa, Japan

were highly resistant to cefaclor, cefpodoxime, cefteram, cefdinir, clarithromycin, ampicillin, and minocycline, but susceptibile to ofloxacin and cefditoren (CDTR). The invitro activity of CDTR was superior to that of other cephalosporins, such as cefaclor, cefdinir, and cefpodoxime, when tested against both the β-lactamase-positive and -negative H. influenzae isolated. CDTR was also active against all the other strains, including methicillin-sensitive S. aureus, S. pyogenes, and M. catarrhalis. This study suggested that CDTR was a useful oral antibiotic for pediatric respiratory tract infections. Key words Penicillin-resistant Streptococcus pneumoniae · Haemophilus influenzae · Respiratory tract infection · Cefditoren · Multidrug resistance

Introduction The bacteria Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Staphylococcus aureus, and Moraxella catarrhalis are responsible for various upper and lower respiratory tract infections, including otitis media in children. The emergence and spread of β-lactamase producing H. influenzae and M. catarrhalis, as well as methicillin-resistant S. aureus (MRSA) have caused great concern clinically. Furthermore, a rapid increase in penicillin-resistant pneumococci has recently been reported in most parts of the world.1,2 Since penicillin-resistant bacteria are becoming less susceptible to other commonly prescribed oral antimicrobial drugs, including tetracycline, erythromycin, and extended-spectrum cephalosporins, the emergence of these pathogens has made treatment difficult.3–5 We undertook this study to determine the prevalence of penicillin resistance in S. pneumoniae and the in-vitro activity of oral antimicrobial agents. To this end, we isolated strains from cultures of pharyngeal swabs in children with acute bacterial respiratory infections and determined their

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minimum inhibitory concentrations (MICs) for antimicrobial agents.

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Results Patient characteristics

Patients and methods Patient population The patients evaluated in this study were children younger than 15 years of age with bacterial respiratory infections, including pharyngitis, tonsillitis, and bronchitis. The children received treatment at the outpatient services of Kanazawa University Hospital and ten other hospitals in Ishikawa Prefecture, Japan, during the period April 1996 through December 1997. Bacterial isolates Pharyngeal swab specimens were cultured and S. pneumoniae, H. influenzae, S. pyogenes, S. aureus, and M. catarrhalis were isolated. In addition, β-lactamase production by H. influenzae and M. catarrhalis was assessed using nitrocephin-impregnated paper disks (Cefinase disks; BBL, Cockeysiville, MD). Antimicrobial susceptibility testing The minimum inhibitory concentrations (MICs) of these isolates for the ten oral antibiotics listed below were determined by the broth microdilution method, according to the standard methods of the Japan Society of Chemotherapy. The antibiotics were: cefditoren (CDTR; Meiji Seika, Tokyo Japan), cefaclor (CCL; Shionogi, Osaka, Japan), cefpodoxime (CPDX; Sankyo, Tokyo, Japan), cefteram (CFTM; Toyama Chemical, Tokyo, Japan), cefdinir (CFDN; Fujisawa Pharmaceutical, Osaka, Japan), clarithromycin (CAM; Taisho Pharmaceutical, Tokyo, Japan), ofloxacin (OFLX; Daiichi Pharmaceutical, Tokyo, Japan), ampicillin (ABPC; Meiji Seika), minocycline (MINO; Lederle Japan, Tokyo, Japan), and penicillin G (PCG; Meiji Seika). The sensitivity of S. pneumoniae to penicillin was classified as follows, in compliance with the recommendation of the United States National Committee for Clinical Laboratory Standards.6 Organisms with an MIC of #0.06 µg/ml were defined as PCG-susceptible S. pneumoniae (PSSP), those with an MIC of 0.125–1.0 µg/ml as PCG-intermediate S. pneumoniae (PISP), and those with an MIC of $2.0 µg/ml as PCG-resistant S. pneumoniae (PRSP). We used the antibiotic breakpoint MIC to discriminate between susceptible and nonsusceptible strains, in accordance with the guidelines of the Japanese Chemotherapy Committee for Sensitivity Determination of Respiratory Infection (pneumonia).7 When the MIC of a drug was lower than the breakpoint MIC, the strain was regarded as susceptible to the drug tested, and the ratio of the susceptible to the nonsusceptible strains was expressed as the susceptibility rate.

Of 301 children from whom cultures were obtained from the pharynx, 245 children from whom identified or suspected causative organisms were isolated were regarded as having bacterial respiratory infections and included in the subsequent analysis. The characteristics of the enrolled patients were: 147 males and 98 females; the symptoms of infection was mild in 166 patients, moderate in 71 patients and inaccessible in 8 patients; age was 0–3 years in 100 patients, 4–7 years in 119 patients, and 8–12 years in 26 patients; diagnosis was pharyngitis in 115 patients, tonsillitis in 69 patients, and bronchitis in 61 patients. Two hundred and seventeen children received antibacterial therapy, of whom 197 had received no previous medication for the infection. Isolation of bacteria As shown in Table 1, from the 245 children with bacterial infections, 119 strains of H. influenzae, 89 strains of S. pyogenes, 61 strains of S. pneumoniae, 36 strains of S. aureus, and 34 strains of M. catarrhalis were isolated. Fiftythree of these children had mixed bacterial cultures. Of the 61 patients from whom S. pneumoniae isolates were obtained, 27 patients had single infections, 29 patients had multiple infections with H. influenzae, and 5 patients had mixed infections with other bacteria. Six strains (23.1%) of S. aureus were MRSA. Of the 74 H. influenzae strains, 11 strains (14.9%) produced β-lactamase. All strains of M. catarrhalis were found to produce β-lactamase. Frequency of penicillin-resistant S. pneumoniae Figure 1 shows the MICs distribution of 61 strains of S. pneumoniae for PCG. There were 17 strains (27.9%) of PSSP, 36 strains (59.0%) of PISP, and 8 strains (13.1%) of PRSP. The overall prevalence of penicillin-resistant S. pneumoniae was thus 72.1%. For children 0–4 years of age, PISP and PRSP represented 89% of the strains isolated, Table 1. Pathogens in respiratory tract infections in 245 children Organism

No. of strains (%)

H. influenzae S. pyogenes S. pneumoniae (PSSP) (PISP) (PRSP) S. aureus M. catarrhalis

119 (35.1) 89 (26.3) 61 (18.0) 17 (27.9a) 36 (59.0a) 8 (13.1a) 36 (10.6) 34 (10.0)

Total

339 (100)

a

Percent age of S. pneumoniae. PSSP, Penicillin-susceptible S. pneumoniae; PISP, penicillin intermediately resistant S. pneumoniae; PRSP penicillin-resistant S. pneumoniae.

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Fig. 1. Minimum inhibitory concentration (MIC) frequency distribution for penicillin against S. pneumoniae. S. pneumoniae with an MIC of #0.06 µg/ml were defined as penicillin-susceptible S. pneumoniae (PSSP; hatched columns), those with an MIC of 0.125–1.0 µg/ml as penicillin-intermediately resistant S. pneumoniae (PISP; gray columns) and those with an MIC of $2.0 µg/ml as penicillin-resistant S. pneumoniae (PRSP; black columns)

Fig. 2. Age distribution of patients from whom S. pneumoniae were recovered. Pharyngeal swab specimens obtained from children with acute bacterial respiratory infections were cultured, and PSSP, PISP, PRSP, and other bacteria (white columns; H. influenzae, S. pyogenes, S. aureus, and M. catarrhalis) were isolated. Hatched, gray, and black columns, as in Fig. 1

Table 2. Antimicrobial susceptibilities of penicillin-resistant S. pneumoniae isolates Antimicrobial agent

CDTR CCL CPDX CFTM CFDN CAM OFLX ABPC MINO

Susceptibility breakpont MIC (µg/ml)a

1 1 1 0.5 1 1 2 0.5 1

PSSP (n 5 17)

PISP (n 5 36)

MIC (µg/ml)

% Susceptible

MIC50

MIC90

Range

#0.03 0.5 0.06 #0.03 0.06 0.06 2 #0.03 0.06

0.25 2 1 0.5 0.25 4 2 0.06 $4

#0.03–0.25 0.25–2 #0.03–1 #0.03–0.5 #0.03–0.5 #0.03–.4 1–2 #0.03–0.06 #0.03–.4

100 88.2 100 100 100 87.5 100 100 64.7

PRSP (n 5 8)

MIC (µg/ml)

% Susceptible

MIC50

MIC90

Range

0.5 .4 2 1 2 1 1 1 4

0.5 .4 2 1 4 .4 2 2 .4

0.125–1 2–.4 0.25–4 #0.03–1 0.5–4 #0.03–.4 1–2 0.06–2 0.25–.4

100 0 19.4 30.6 16.7 60.7 100 30.6 8.3

MIC (µg/ml)

% Susceptible

MIC50

MIC90

Range

0.5 .4 2 1 4 2 1 2 4

1 .4 4 1 .4 2 2 4 .4

0.5–1 .4 2–4 1 4–.4 1–2 1–2 1–4 0.25–.4

100 0 0 0 0 25 100 0 12.5

MIC, Minimum inhibitory concentration; CDTR, ceftidoren; CCL, cefaclor; CPDX, cefpodoxime; CFTM, cefteram; CFDN, cefdinir; CAM, clarithromycin; OFLX, ofloxacin; ABPC, ampicillin; MINO, minocycline. a Based on Japanese Chemotherapy Committee guidelines.7

while the corresponding rate for children over 5 years of age was 14% (Fig. 2). Susceptibility testing The distribution of the MIC, MIC50, and MIC90, and the susceptibility of S. pneumoniae to the nine antimicrobials (excluding PCG) are shown in Table 2. All drugs except for MINO showed potent activity against PSSP. CDTR was active against PISP and PRSP, with MICs ranging from 0.125 to 1 µg/ml and 0.5 to 1 µg/ml, respectively. On the basis of the breakpoints defined by the Japanese Chemotherapy Committee, about 60% of PISP strains were susceptible to the newer macrolide CAM. PISP and PRSP showed resistance to all the drugs tested, except for CDTR and OFLX. The in-vitro activities of the nine antimicrobial agents against isolates other than S. pneumoniae are summarized in Table 3. Although the MIC of CDTR against MRSA was 2.0 µg/ml or higher (data not shown), this drug showed very high activity against all the other strains, including

methicillin-sensitive S. aureus (MSSA) and H. influenzae, regardless of whether or not they produced β-lactamase. OFLX also showed high antibacterial activity against a broad spectrum of organisms. Resistance to CCL occurred in most of the strains tested, except for S. pyogenes. None of the strains of H. influenzae were susceptible to CAM. On the basis of the breakpoints, 44.4% of β-lactamase-negative H. influenzae were found to show intermediate resistance (MICs $1 µg/ml) to ABPC. Other antibiotics of the cephem class (i.e., CPDX, CFTM, CFDN) were not active against some of the strains of H. influenzae and M. catarrhalis.

Discussion The emergence of penicillin resistance in clinical isolates of S. pneumoniae represents a compelling problem for pediatricians.8,9 The Japanese Working Group for PenicillinResistant S. pneumoniae reported that the prevalence of PISP/PRSP among S. pneumoniae isolates approached 40%

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Table 3. Susceptibility of bacterial pathogens other than S. pneumoniae Antimicrobial agent

CDTR CCL CPDX CFTM CFDN CAM OFLX ABPC MINO

H. influenzae (BL2)a (n 5 63)

H. influenzae (BL1)b (n 5 11)

MIC50 (µg/ml)

MIC90

%Susc.d

MIC50

MIC90

%Susc.

#0.03 .4 0.125 #0.03 0.5 .4 #0.03 0.5 0.25

0.06 .4 1 0.125 4 .4 0.06 2 0.5

100 9.5 90.5 98.4 73 0 100 55.6 96.8

#0.03 4 0.125 #0.03 1 4 #0.03 .4 0.5

0.06 .4 0.5 0.06 4 .4 0.06 .4 1

100 18.2 100 100 72.7 0 100 0 100

S. pyogenes (n 5 48)

S. aureusc (n 5 20)

M. catarrhalis (n 5 28)

MIC50

MIC90

%Susc.

MIC50

MIC90

%Susc.

MIC50

MIC90

%Susc.

#0.03 0.06 #0.03 #0.03 #0.03 #0.03 1 #0.03 0.06

#0.03 0.125 #0.03 #0.03 #0.03 1 1 #0.03 2

100 100 100 100 100 95.8 97.9 100 85.4

0.5 2 4 2 0.5 0.5 0.5 1 0.125

1 4 .4 4 0.5 .4 1 1 0.125

100 10 0 0 100 75 95 15 100

0.5 4 2 2 0.25 0.125 0.06 4 0.25

1 .4 2 2 0.5 0.5 0.125 .4 0.25

96.4 28.6 32.1 14.3 100 100 100 3.6 100

β-Lactamase non-producing strains. β-Lactamase producing strains. Methicillin-sensitive strains. d % Susceptible, using breakpoint criteria, based on Japanese Chemotherapy Committee guidelines. a

b c

in 1994.10,11 In this present study, although the number of isolates evaluated was small, results indicate a high incidence of penicillin-resistance in clinical isolates of S. pneumoniae from children with respiratory tract infection in Japan. The overall prevalence of penicillin-resistant S. pneumoniae was 72.1%, and this increase was noted mainly for strains showing intermediate resistance. The frequency of resistant isolates was higher in children aged less than 4 years. PISP/PRSP was recovered more frequently from patients with bronchitis (data not shown). Zenni et al.12 reported that children younger than 2 years of age had a twofold higher percentage of resistant isolates than those older than 2 years. Clinically, the pneumococcal organisms colonizing the nasopharynx reflect the isolates associated with local or systemic infections, and their antibiotic susceptibilities should reflect the overall penicillin susceptibility of pneumococci causing infections in the patients evaluated. The resistance of S. pneumoniae to penicillin results from alterations in penicillin-binding proteins (PBPs), enzymes that are involved in the synthesis of the bacterial cell wall.13,14 Thus, the reduction of susceptibility to penicillin is invariably associated with a reduced susceptibility to all other β-lactam antibiotics. High-level resistance to the extended-spectrum cephalosporins (i.e., cefotaxime or ceftriaxone) is also mediated through the PBPs. S. pneumoniae may acquire resistance to non-β-lactam antibiotics through conjugation with other streptococci, which leads to changes in target sites (e.g., for macrolides, trimethoprim, and fluoroquinolones) or inactivating enzymes (e.g., for chloramphenicol). On the basis of the breakpoints defined by the Japanese Chemotherapy Committee, the activities of all oral β-lactam antibiotics we tested, except for CDTR, were reduced for most strains of PISP and PRSP. PISP and PRSP strains were also less susceptible to non-β-lactam antibiotics, i.e., CAM, a 14membered macrolide, and MINO. It has been reported that S. pneumoniae were highly resistant to erythromycin, a 14membered macrolide, but susceptible to rokitamycin, a 16membered macrolide.15 The other etiologic agents causing acute respiratory tract infection (including otitis media) in children in our

sample were H. influenzae, S. pyogenes, S. aureus, and M. catarrhalis. According to the ampicillin breakpoint of $1 µg/ml, 44.4% of β-lactamase non-producing H. influenzae strains were found to be intermediately resistant to ABPC.16,17 The result of this study confirms the impression that β-lactamase-negative, ampicillin-resistant (BLNAR) strains are increasingly prevalent among H. influenzae in Japan.18 CDTR was active against H. influenzae, regardless of whether or not they produced βlactamase, whereas CAM had a lower MIC than the breakpoint MIC in all strains. All clinical isolates of M. catarrhalis produced β-lactamase and were considered to be probably resistant to ABPC.19 M. catarrhalis were susceptible to CDTR and CFDN, but not to the other cephalosporins tested. CDTR was developed in Japan and has excellent in-vitro activity against the major respiratory pathogens commonly associated with childhood respiratory tract infections, as discussed above.20–23 Consequently children with highly PRSP strains may be a unique subset more refractory to treatment not only because of they harbor the less susceptible organisms but also because of additional host factors, such as age-dependent immunologic differences. Further, the presence of healthy carriers with PISP/PRSP has become an important problem in outpatients and among staff and children in child-care centers.12 CDTR was thus considered a useful oral antibiotic for respiratory tract infection in children, including infections with multi-resistant PISP and PRSP and BLNAR H. influenzae. However, further studies are required to determine the optimal oral antibiotic choices and duration of therapy for outpatients with mild pneumococcal infections caused by PRSP.24,25 In addition, continuous surveillance of carriage of PRSP and clinical awareness of other resistant strains of H. influenzae and M. catarrhalis is necessary. Acknowledgments We thank the following individuals for providing the clinical data and clinical isolates of bacterial organisms: Drs. Y. Kobayashi (West Kanazawa Hospital), N. Okuda (Kanazawa National Hospital), T. Nagaoki (Naruwa Hospital), S. Seishu (Noto Public Hospital), T. Funahashi (Kanazawa Municipal Hospital), K. Honke (Io National Hospital), Y. Ueno (Komatsu Municipal Hospital),

20

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K. Iwai (Wajima Municipal Hospital), and H. Wada (Suzu Municipal Hospital). 13. 14.

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