JAC Advance Access originally published online on January 28, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 721-725
© 2003 The British Society for Antimicrobial Chemotherapy
Faropenem, a new oral penem: antibacterial activity against selected anaerobic and fastidious periodontal isolates
Department of Microbiological and Gynaecological Sciences—Section of Microbiology, University of Catania, Via Androne 81, 95124 Catania, Italy
Received 3 September 2002; returned 24 September 2002; revised 10 December 2002; accepted 13 December 2002
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Abstract |
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The in vitro activity of faropenem, an oral penem, was compared with those of penicillin, co-amoxiclav, cefoxitin, clindamycin, erythromycin and metronidazole against 106 isolates of anaerobic pathogens involved in systemic infections. The organisms tested comprised Porphyromonas gingivalis (29), Prevotella spp. (eight), Prevotella melaninogenica (seven), Prevotella intermedia (five), Actinomyces spp. (25), Fusobacterium nucleatum (14), Peptostreptococcus spp. (11), Bacteroides ureolyticus (five) and Bacteroides forsythus (two). The antimicrobial properties of faropenem were investigated by studying MICs, MBCs, time–kill kinetics and post-antibiotic effect (PAE). Faropenem was highly active against all the anaerobes tested (MIC90
0.5 mg/L) and was bactericidal against both ß-lactamase-positive and -negative anaerobes, with a maximum bactericidal effect at 10 x MIC at between 12 and 24 h. In addition, faropenem had an in vitro PAE on all the tested isolates and this was not influenced by ß-lactamase production. Faropenem may be useful for treating infections caused by periodontal bacteria or oral flora. Keywords: faropenem, anaerobic pathogens, antibacterial activity
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Introduction |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Periodontal anaerobic pathogens are often associated with various infections, including systemic illnesses such as bacteraemia, endocarditis, brain abscesses, urogenital, skin and soft tissue, pulmonary, gastrointestinal and urogenital infections.1,2 The different susceptibilities of these pathogens to antimicrobial agents make therapy very difficult.3,4
Faropenem is a unique antimicrobial penem being developed for oral administration as the pro-drug ester, faropenem-daloxate. Penems share structural similarities with both penicillins and cephalosporins, and are characterized by a broad antibacterial spectrum, a potent penicillin-binding protein affinity and good ß-lactamase stability.5–7
The aim of this study was to evaluate the antibacterial activity of faropenem in comparison with that of other antibiotics against anaerobic pathogens involved in systemic infections, and to evaluate the in vitro pharmacodynamic properties of faropenem by studies of time–kill kinetics and post-antibiotic effect (PAE).
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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Microorganisms
We tested 106 recent isolates collected from periodontal infections: Porphyromonas gingivalis (29), Prevotella spp. (eight), Prevotella melaninogenica (seven), Prevotella intermedia (five), Actinomyces spp. (25), Fusobacterium nucleatum (14), Peptostreptococcus spp. (11), Bacteroides ureolyticus (five) and Bacteroides forsythus (two). The identification of bacteria was made by colony and cellular morphology, staining characteristics, motility test and biochemical tests.8,9 Further bacterial identifications were carried out using API 20A, API-ZYM and rapid ID32A (bioMérieux).
All isolates with penicillin MICs 
0.25 mg/L were tested for production of ß-lactamase by spreading fresh (24–48 h) cultures on filter paper moistened with 500 mg/L nitrocefin.
Antibiotics
The antibacterial activity of faropenem was studied in comparison with that of penicillin G (Pharmacia), co-amoxiclav (SmithKline Beecham), cefoxitin (Merck, Sharp & Dôhme), erythromycin (Abbott), clindamycin (Upjohn) and metronidazole (Bristol-Myers Squibb). The agents tested, as powders of known potency, were gifts from their respective manufacturers.
Determination of MICs and MBCs
MICs of faropenem and of the other antimicrobials in the comparison were determined by the microdilution method using Brucella broth supplied with haemin (0.005 mg/L) and vitamin K1 (0.0004 ml/L) with an inoculum of 105 cfu/mL, in accordance with the guidelines of the NCCLS.10 Bacteroides fragilis ATCC 25285 was used as a control strain. The MIC was defined as the lowest concentration at which there was no visible growth after incubation at 35–37°C for 48 h.
The susceptibility breakpoints recommended by the NCCLS for anaerobic bacteria were: penicillin 0.5 mg/L, co-amoxiclav 4/2 mg/L, cefoxitin 16 mg/L, clindamycin 2 mg/L and metronidazole 8 mg/L. For erythromycin, the value of 0.5 mg/L was used according to the recommendations for aerobic bacteria.11 NCCLS breakpoints for faropenem are not yet available.
After the determination of faropenem MICs, subcultures onto supplemented Brucella agar were obtained from the wells devoid of growth by means of a 6 mm loop. Incubation was carried out at 35–37°C in anaerobic jars for 48 h. The MBC was defined as the lowest antibiotic concentration resulting in no visible colony growth.
Time–kill kinetics
The killing curves of faropenem and co-amoxiclav were carried out in accordance with the method of Rosenblatt,12 against two isolates each of P. gingivalis, B. ureolyticus and Actinomyces spp. and one isolate of Prevotella sp. and F. nucleatum. In a closed system the bacteria were incubated with faropenem at concentrations equivalent to the MIC, 4 x and 10 x MIC, and with co-amoxiclav at MIC and 4 x MIC. Bactericidal activity was defined as a 3 log10 decrease (99.9% kill) in cfu/mL.
PAE
The PAE of faropenem was determined by the viable plate count method of Craig & Gudmundsson13 against eight isolates of periodontal bacteria: two isolates each of P. gingivalis (CT 12 ß-lac+, MIC 0.125 mg/L and CT 23 ß-lac–, MIC 0.25 mg/L), B. ureolyticus (CT 21 ß-lac–, MIC 0.06 mg/L and CT 42 ß-lac+, MIC 0.06 mg/L), Actinomyces sp. (CT 10 ß-lac–, MIC 0.06 mg/L and CT 25 ß-lac–, MIC 0.125 mg/L), Prevotella sp. (CT 7 ß-lac–, MIC 0.06 mg/L) and F. nucleatum (CT 2 ß-lac–, MIC 0.125 mg/L).
The PAE was determined in duplicate on supplemented Brucella agar at faropenem concentrations of 4 x and 10 x MIC. A significant PAE was defined as an effect of >0.5 h.
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Results and discussion |
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TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
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The in vitro activities of the drugs tested against 106 isolates are shown in Table 1.
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ß-Lactamase production in isolates of B. forsythus (50%), B. ureolyticus (20%), Prevotella spp. (20%), F. nucleatum (7%) and P. gingivalis (3%) compromised the activity of penicillin (MIC
1 mg/L). Faropenem had significant activity (MIC90 0.5 mg/L) against both ß-lactamase-producing and -non-producing isolates. B. forsythus isolates were inhibited by faropenem concentrations of 0.06 and 0.12 mg/L, and B. ureolyticus by concentrations ranging from 0.03 to 0.5 mg/L. ß-Lactamase-positive isolates remained susceptible to co-amoxiclav and cefoxitin (MIC 4 mg/L). Erythromycin was generally less active than faropenem, in particular against F. nucleatum, Peptostreptococcus spp., B. forsythus and B. ureolyticus. Good activity was observed for clindamycin, particularly against Prevotella spp. (MIC range 0.03– 2 mg/L) and F. nucleatum (MIC range 0.06–0.25 mg/L). The majority of all tested species were inhibited by metronidazole at 8 mg/L, except for Actinomyces spp. (MIC range 8–>64 mg/L).
Since breakpoint interpretative criteria for faropenem have not been established for anaerobic bacteria, our study does not report percentage susceptibility. The overall percentage of isolates susceptible to penicillin was 91%. Except for Peptostreptococcus spp. (91%), all the species tested were susceptible to co-amoxiclav and cefoxitin (100%). The percentage of susceptibility to clindamycin of all isolates tested was 95%, whereas the susceptibility to metronidazole was 100%, except for Actinomyces spp. (34%). Using the value of 0.5 mg/L, according to the recommendations for aerobic bacteria,12 the overall susceptibility percentage to erythromycin was 77%; however, the activity of erythromycin can be affected by anaerobic conditions, mainly when fusobacteria are tested.
MBCs of faropenem were equal to or 2–4 x higher than MICs.
Against the isolates of P. gingivalis and Actinomyces spp. (Figure 1a–d), faropenem exhibited a bactericidal activity at 10 x MIC at 12 h, whereas against B. ureolyticus and F. nucleatum (Figure 1e–g) a bactericidal effect was observed at 24 h.
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Faropenem had an efficient killing activity against Prevotella spp. (Figure 1h) at both 10 x and 4 x MIC, which compared favourably with that of co-amoxiclav.
For P. gingivalis and Actinomyces spp. isolates, co-amoxiclav at 10 x MIC was bactericidal at 12 h (Figure 1a–d). At 4 x MIC, co-amoxiclav exerted a bactericidal effect at 8 h against Actinomyces spp. (Figure 1c and d) and at 12 h against B. ureolyticus CT 42 (Figure 1e).
Unlike most ß-lactams, faropenem exhibited an in vitro PAE on some clinically relevant anaerobic bacteria, and this effect was not influenced by ß-lactamase production.13 Generally, increasing concentrations of faropenem were associated with increases in the PAE. The PAE was marked for P. gingivalis both at 4 x and 10 x MIC. However, in all cases the greatest effect was observed at 10 x MIC. The shortest PAE was observed for Actinomyces spp. at both 4 x and 10 x MIC (Table 2). The differences in PAE duration at 4 x and 10 x MIC of faropenem were not significant, except for Actinomyces spp., against which 10 x MIC produced a PAE two to three times longer than that obtained at 4 x MIC.
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Our results show that faropenem has potent antibacterial activity against periodontal pathogens comparable to that of cefoxitin and co-amoxiclav, and higher than that of clindamycin and metronidazole. The time–kill kinetics showed that faropenem was bactericidal against both ß-lactamase-positive and -negative anaerobic bacteria, and appeared to exhibit time-dependent bactericidal activity, which is usual for ß-lactams. The performance of faropenem in the present study, in addition to its broad spectrum of activity and its stability to ß-lactamases, makes it a promising new antimicrobial agent in anaerobic or mixed infections.
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Acknowledgements |
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We would like to thank Professor A. Dalhoff for his advice and support. These investigations were funded by Bayer AG, Germany.
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Footnotes |
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* Corresponding author. Tel: +39-095-312386; Fax: +39-095-325032; E-mail: special{at}mbox.unict.it
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References |
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