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Hiroshige Mikamo, MD, PhDDepartment of Obstetrics and GynecologyGifu University, School of Medicine40, Tsukasa-machi, Gifu city, Gifu 500-8705 (Japan)Tel. +81 58 267 2631, Fax +81 58 265 9006

Microbiology

Chemotherapy 1998;44:328–330

In vitro Activities of E1101, a Novel OralCephalosporin, against Bacteria CausingInfections in Obstetric andGynecological Patients

Hiroshige MikamoYasumasa SatoYoh HayasakiKyoko KawazoeTeruhiko Tamaya

Department of Obstetrics andGynecology, Gifu University,School of Medicine, Gifu, Japan

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Key WordsE1101E1100Cefdinir (CFDN)Minimal inhibitory

concentration

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AbstractE1101 is a new oral cephalosporin with a broad spectrum ofantibacterial activity. It inhibited more than 90% of clinicalisolates of Streptococcus agalactiae, Escherichia coli and Pep-tostreptococcus magnus at the concentration of 3.13 mg/l.E1101 was the most active agent against S. agalactiae andE. coli. Since none of the compounds was sufficiently activeagainst the Bacteroides fragilis and Prevotella bivia isolates,they are not appropriate in the treatment of patients withinfections caused by these organisms. The results of this studysuggest that, subject to confirmation by clinical trials, E1101,in combination with an agent with reliable activity againstanaerobic bacteria, is suitable as empirical therapy of patientswith obstetric and gynecological infections.OOOOOOOOOOOOOOOOO

Introduction

E1101 is a new oral cephalosporin with thechemical structure:

(RS)-1-(isopropoxycarbonyloxy)ethyl(+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyimino-acetamido]-3-N,N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car-boxylate monohydrochloride.

The active form is E1101 with the chemi-cal structure:

(+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcar-bamoyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

The drug was first synthesized by Eisai,Tokyo, Japan [1, 2], and has been shown tohave potent, broad-spectrum in vitro activitywhen compared with those of closely relatedcephalosporins. The aim of the present studywas to assess the in vitro activity of E1101against clinical isolates from patients with ob-

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In vitro Activities of E1101 Chemotherapy 1998;44:328–330 329

Table 1. In vitro antimicrobialactivity of E1100, cefdinir,cefpodoxime and cefaclor againstclinical isolates in the fields ofobstetrics and gynecology

Organism(no. of strains)

Compound MIC, Ìg/ml

range 50% 90%

S. agalactiae (20) E1100cefdinircefpodoximecefaclor

0.0125–1.560.025–1.560.025–3.13

0.0125–0.78

0.0250.050.051.56

0.050.050.053.13

E. coli (20) E1100cefdinircefpodoximecefaclor

!0.0125–0.78!0.0125–1.56!0.0125–3.13!0.0125–6.25

0.0250.100.101.56

0.050.390.393.13

P. magnus (20) E1100cefdinircefpodoximecefaclor

0.025–6.250.0125–12.50.0125–250.0125–50

0.780.200.203.13

3.131.563.13

25

B. fragilis (20) E1100cefdinircefpodoximecefaclor

0.20–11000.39–11001.56–11006.25–1100

6.256.256.2512.5

100110011001100

P. bivia (20) E1100cefdinircefpodoximecefaclor

0.78–11000.78–11001.56–11006.25–1100

6.256.2512.5

1100

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Inoculum size: 2.5 ! 104 CFU/spot.

stetric or gynecological infections and to com-pare these activities with those of other oralcephalosporins; the organisms selected in-cluded pathogens that are important in thisclinical setting, but against which the activi-ties of E1101 have not been evaluated pre-viously.

Materials and Methods

Antimicrobial Agents. The antibiotics studied wereE1101, cefaclor (Shionogi, Osaka, Japan), cefdinir (Fu-jisawa, Osaka, Japan) and cefpodoxime (Sankyo, To-kyo, Japan).

Strains Tested. A total 100 recent clinical isolates(40 strains of aerobes and 60 strains of anaerobes) werecollected from patients in the Department of Obstet-

rics and Gynecology, Gifu University, School of Medi-cine, during the period between January and Decem-ber 1996. The aerobes were identified by the APISTREP system (API System, Montalieu-Vercieu,France) and the Enterotube II system (Becton Dickin-son, Cockeysville, Md., USA) and anaerobes by theRap ID ANA system II (Innovative Diagnosis System,Atlanta, Ga., USA). The isolates included 20 strainseach of Streptococcus agalactiae, Escherichia coli, Pep-tostreptococcus magnus, Bacteroides fragilis and Prevo-tella bivia.

Susceptibility Tests. Minimal inhibitory concentra-tions (MICs) were determined by an agar dilutionmethod [3, 4]. Aerobic and anaerobic organisms weregrown on agar plates [Mueller-Hinton agar (Difco Lab-oratories, Detroit, Mich., USA) for aerobes, GAM(Gifu Anaerobic Medium) agar (Nissui, Tokyo, Japan)for P. magnus and B. fragilis, and Brucella HK agar(Kyokuto, Tokyo, Japan) supplemented with 5% lakedsheep blood for P. bivia] were suspended in Mueller-

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330 Chemotherapy 1998;44:328–330 Mikamo/Sato/Hayasaki/Kawazoe/Tamaya

Hinton broth (Difco) and GAM broth (Nissui), respec-tively, to obtain about 5 ! 108 CFU/ml. After a 200-fold dilution of the suspension, the bacteria were trans-ferred to agar plates containing each antimicrobialagent (0.0125–100 mg/l) with a multipoint inocular(Microplanter, Sakuma Seikusho, Tokyo, Japan) at acell density of about 2.5 ! 104 CFU/spot. Mueller-Hinton agar (Difco) was used for aerobes and BrucellaHK agar (Kyokuto) supplemented with 5% lakedsheep blood for anaerobes. All aerobic cultures wereincubated at 37 °C for 24 h and all anaerobic culturesat 37°C for 72 h in a Gas Pak system (Becton Dickin-son). MICs were defined as the lowest concentrationsof antimicrobial agents that prevented the visiblegrowth of organisms.

Results and Discussion

Table 1 shows the MICs of four antibioticsfor the strains tested. E1101 was the mostactive agent against S. agalactiae and E. coli.None of the compounds was sufficiently ac-tive against the B. fragilis and P. bivia isolates;consequently they are not applicable in thetreatment of patients with infections causedby these organisms. The results of this studysuggest that, subject to confirmation by clini-cal trials, E1101, in combination with anagent with reliable activity against anaerobicbacteria, is suitable as empirical therapy ofpatients with obstetric and gynecological in-fections.

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References

1 Negi S, Yamanaka M, Sugiyama I,Komatsu Y, Sasho M, Tsuruoka A,Kamada A, Tsukada I, Hiruma R,Katsu K, Machida Y: Studies onorally active cephalosporins. I. Syn-thesis and structure-activity rela-tionships of new 3-substituted car-bamoyloxymethyl cephalosporins. JAntibiot 1994;47:1507–1525.

2 Negi S, Komatsu Y, Tsuruoka A,Uemura Y: Synthesis of a radiola-belled new oral cephalosporin,E1101. J Labelled Compounds Ra-diopharm 1995;38:1–11.

3 National Committee for ClinicalLaboratory Standards: Methods forDilution Antimicrobial Susceptibili-ty Testing for Bacteria that GrowAerobically, ed 2, NCCLS Docu-ment M7-A2, vol 10, No 8, 1990.

4 National Committee for ClinicalLaboratory Standards: Methods forDilution Antimicrobial Susceptibili-ty Testing of Anaerobic Bacteria,ed 2, approved standard M11-A2,NCCLS Document M11-A2, vol 10,No 15, 1990.