946
Eur. J. Clin. Microbiol. Infect. Dis.
_u u
Comparative in Vitro Activity of Ro 40-6890, Ro 41-3399, and Other Antimicrobial Agents against Anaerobic Bacteria J. Wrist*, U. H a r d e g g e r Ro 41-3399 The in vitro activity of the ester Ro 41-3399 and its free active acid Ro 40-6890 was tested against 189 strains of anaerobic bacteria in comparison to other oral cephalosporins and to antimicrobial agents established in the treatment of anaerobic infections. Prevotella, Porphyromonas, Peptostreptococcus, Fusobacterium and Clostridium spp. were susceptible to Ro 40-6890, with few exceptions. Due to its lack of activity against the major pathogens of the Bacteroides fragilis group, Ro 40-6890 does not promise to be of major use in the treatment of infections caused by anaerobes.
Most potent cephalosporins are poorly absorbed from the human intestinal tract and are therefore suited only for parenteral use. However, some of these compounds are well absorbed in the form of ester derivatives. Ro 41-3399 is a new orally administered ester of Ro 40-6890, a third-generation cephalosporin; the chemical structure of both compounds is shown in Figure 1. Ro 41-3399 is currently under clinical investigation. We report on the in vitro activity of both Ro 41-3399 and its free acid Ro 40-6890 against 189 strains of anaerobic bacteria isolated from patients with systemic infections in comparison to other oral cephalosporins and to antimicrobial agents established in the treatment of anaerobic infections. Materials and Methods. The following antimicrobial agents were tested: Ro 41-3399, Ro40-6890, cefetamet (Hoffmann-La Roche, Switzerland), cefaclor (Eli Lilly, USA), cefixime (Merck Darmstadt, FRG), cefoxitin (Merck, Sharp and Dohme, USA), cefuroxime (Glaxo, UK), amoxicillin and amoxiciltin/clavulanic acid (Beecham, UK), chloramphenicol (Parke-Davis, USA), clindamycin (Upjohn, USA) and metronidazole (Specia, France). Department of Medical Microbiology, University of Zurich, Gloriastrasse 32, CH-8028 Ziirich, Switzerland.
s
)
o
i
113
3 Na ~ O"-
~'O
Ro 40-6890 sodium Figure 1: Chemical
structures
of Ro 41-3399 and
Ro 40-6890. The 189 bacterial strains tested (Table 1) were isolated in 1989 from clinical specimens and identified using the RapidAna II (Innovative Diagnostic Systems, USA) or ATB 32A (API, France) systems combined with gas-liquid chromatography of volatile and non-volatile fatty acids from PRAS chopped-meat broth containing carbohydrates (1). MICs were determined by the NCCLS agar dilution method (2) on WilkinsChalgren agar (BBL, USA) using an inoculum of approximately 105 organisms per spot derived from a fresh culture in supplemented thioglycolate broth (135C, BBL) as recommended by the NCCLS (2). The plates were incubated for 42 h in an anaerobic chamber (Coy, USA) filled with a gas mixture of 10 % hydrogen, 5 % carbon dioxide and 85 % nitrogen. The quality control strains Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741 and Clostridium pelfringens ATCC 13124 were included in all runs; MICs corresponded to the established values where available (2). Results and Discussion. The results are shown in Table 1. All orally administered cephalosporins showed poor activity against Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides ovatus and Bacteroides uniformis. Ro 40-6890 was slightly more active than the other oral cephalosporins tested, but not nearly as active as amoxicillin/
V o l . 11, 1 9 9 2
947
Table 1: Activity of R o 40-6890, R o 41-3399 and o t h e r antimicrobiat agents against a n a e r o b i c bacteria. Organism (n)
Antimicrobial agent
Bacteroides fragilis (48)
Bacteroides fragilis g r o u p ( o t h e r than B. fragilis) (47)
Prevotella a n d . Porphyromonas
(30)
spp.
(7)
Range
MIC50
MIC90
R o 40-6890 R o 41-3399 Cefaclor Cefetamet Cefixime Cefoxitin Cefuroxime Amoxicillin Amoxicillin/CA* Chloramphenicol Clindamycin Metronidazole
32 32 > 128 64 64 8 >_.128 32 1 8 2 1
64 64 > 128 > 128 >_.128 16 >_.128 >_128 2 8 _>128 2
4 8 32 16 4 4 4 0.25 0.5 4 0.12 0.25
-
> 128 >_128 2 128 > 128 > 128 32 >_128 128
R o 40-6890 R o 41-3399 Cefac|or Cefetamet Cefixime Cefoxitin Cefuroxime Amoxicillin Amoxicillin/CA* Chloramphenicol Clindamycin Metronidazole
64 > 128 2 128 >_128 -> 128 32 > 128 32 1 8 4 1
> 128 > 128 >_128 >__128 >_128 64 >_128 64 2 8 8 1
2 8 64 8 8 2 4 8 0.25 4 0.06 0.5
-
> 128 > 128 2 128 >_.128 >_128 64 >_.128 64 2 16 32 2
2 >_128 >_128 >_.128 >_128 16 > 128 32 4 8 >_.128 1
,< 0.12 "--128 8 8 _ 128 2
R o 40-6890 R o 41-3399 Cefaclor Cefetamet Cefixime Cefoxitin Cefuroxime Amoxicillin Chloramphenicol Clindamycin Metronidazole
2 8 8 16 4 8 16 1 0.5 4 1 1
R o 40-6890 R o 41-3399 Cefaclor Cefelamet Cefixime Cefoxitin Cefuroxime Arnoxicillin Amoxicillin/CA* Chloramphenicol Clindamycin Metronidazole
_
Eur. J. Clin. Microbiol. Infect. Dis.
_u u
Comparative in Vitro Activity of Ro 40-6890, Ro 41-3399, and Other Antimicrobial Agents against Anaerobic Bacteria J. Wrist*, U. H a r d e g g e r Ro 41-3399 The in vitro activity of the ester Ro 41-3399 and its free active acid Ro 40-6890 was tested against 189 strains of anaerobic bacteria in comparison to other oral cephalosporins and to antimicrobial agents established in the treatment of anaerobic infections. Prevotella, Porphyromonas, Peptostreptococcus, Fusobacterium and Clostridium spp. were susceptible to Ro 40-6890, with few exceptions. Due to its lack of activity against the major pathogens of the Bacteroides fragilis group, Ro 40-6890 does not promise to be of major use in the treatment of infections caused by anaerobes.
Most potent cephalosporins are poorly absorbed from the human intestinal tract and are therefore suited only for parenteral use. However, some of these compounds are well absorbed in the form of ester derivatives. Ro 41-3399 is a new orally administered ester of Ro 40-6890, a third-generation cephalosporin; the chemical structure of both compounds is shown in Figure 1. Ro 41-3399 is currently under clinical investigation. We report on the in vitro activity of both Ro 41-3399 and its free acid Ro 40-6890 against 189 strains of anaerobic bacteria isolated from patients with systemic infections in comparison to other oral cephalosporins and to antimicrobial agents established in the treatment of anaerobic infections. Materials and Methods. The following antimicrobial agents were tested: Ro 41-3399, Ro40-6890, cefetamet (Hoffmann-La Roche, Switzerland), cefaclor (Eli Lilly, USA), cefixime (Merck Darmstadt, FRG), cefoxitin (Merck, Sharp and Dohme, USA), cefuroxime (Glaxo, UK), amoxicillin and amoxiciltin/clavulanic acid (Beecham, UK), chloramphenicol (Parke-Davis, USA), clindamycin (Upjohn, USA) and metronidazole (Specia, France). Department of Medical Microbiology, University of Zurich, Gloriastrasse 32, CH-8028 Ziirich, Switzerland.
s
)
o
i
113
3 Na ~ O"-
~'O
Ro 40-6890 sodium Figure 1: Chemical
structures
of Ro 41-3399 and
Ro 40-6890. The 189 bacterial strains tested (Table 1) were isolated in 1989 from clinical specimens and identified using the RapidAna II (Innovative Diagnostic Systems, USA) or ATB 32A (API, France) systems combined with gas-liquid chromatography of volatile and non-volatile fatty acids from PRAS chopped-meat broth containing carbohydrates (1). MICs were determined by the NCCLS agar dilution method (2) on WilkinsChalgren agar (BBL, USA) using an inoculum of approximately 105 organisms per spot derived from a fresh culture in supplemented thioglycolate broth (135C, BBL) as recommended by the NCCLS (2). The plates were incubated for 42 h in an anaerobic chamber (Coy, USA) filled with a gas mixture of 10 % hydrogen, 5 % carbon dioxide and 85 % nitrogen. The quality control strains Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741 and Clostridium pelfringens ATCC 13124 were included in all runs; MICs corresponded to the established values where available (2). Results and Discussion. The results are shown in Table 1. All orally administered cephalosporins showed poor activity against Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides ovatus and Bacteroides uniformis. Ro 40-6890 was slightly more active than the other oral cephalosporins tested, but not nearly as active as amoxicillin/
V o l . 11, 1 9 9 2
947
Table 1: Activity of R o 40-6890, R o 41-3399 and o t h e r antimicrobiat agents against a n a e r o b i c bacteria. Organism (n)
Antimicrobial agent
Bacteroides fragilis (48)
Bacteroides fragilis g r o u p ( o t h e r than B. fragilis) (47)
Prevotella a n d . Porphyromonas
(30)
spp.
(7)
Range
MIC50
MIC90
R o 40-6890 R o 41-3399 Cefaclor Cefetamet Cefixime Cefoxitin Cefuroxime Amoxicillin Amoxicillin/CA* Chloramphenicol Clindamycin Metronidazole
32 32 > 128 64 64 8 >_.128 32 1 8 2 1
64 64 > 128 > 128 >_.128 16 >_.128 >_128 2 8 _>128 2
4 8 32 16 4 4 4 0.25 0.5 4 0.12 0.25
-
> 128 >_128 2 128 > 128 > 128 32 >_128 128
R o 40-6890 R o 41-3399 Cefac|or Cefetamet Cefixime Cefoxitin Cefuroxime Amoxicillin Amoxicillin/CA* Chloramphenicol Clindamycin Metronidazole
64 > 128 2 128 >_128 -> 128 32 > 128 32 1 8 4 1
> 128 > 128 >_128 >__128 >_128 64 >_128 64 2 8 8 1
2 8 64 8 8 2 4 8 0.25 4 0.06 0.5
-
> 128 > 128 2 128 >_.128 >_128 64 >_.128 64 2 16 32 2
2 >_128 >_128 >_.128 >_128 16 > 128 32 4 8 >_.128 1
,< 0.12 "--128 8 8 _ 128 2
R o 40-6890 R o 41-3399 Cefaclor Cefetamet Cefixime Cefoxitin Cefuroxime Amoxicillin Chloramphenicol Clindamycin Metronidazole
2 8 8 16 4 8 16 1 0.5 4 1 1
R o 40-6890 R o 41-3399 Cefaclor Cefelamet Cefixime Cefoxitin Cefuroxime Arnoxicillin Amoxicillin/CA* Chloramphenicol Clindamycin Metronidazole
_
