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. 2002 Nov;46(11):3669–3675. doi: 10.1128/AAC.46.11.3669-3675.2002

In Vitro Activities of Faropenem against 579 Strains of Anaerobic Bacteria

Hannah M Wexler 1,2,*, Denise Molitoris 2, Shahera St John 2, Ann Vu 2, Erik K Read 2, Sydney M Finegold 1,2,3,4
PMCID: PMC128757  PMID: 12384389

Abstract

The activity of faropenem, a new oral penem, was tested against 579 strains of anaerobic bacteria by using the NCCLS-approved reference method. Drugs tested included amoxicillin-clavulanate, cefoxitin, clindamycin, faropenem, imipenem, and metronidazole. Of the 176 strains of Bacteroides fragilis group isolates tested, two isolates had faropenem MICs of 64 μg/ml and imipenem MICs of >32 μg/ml. Faropenem had an MIC of 16 μg/ml for an additional isolate of B. fragilis; this strain was sensitive to imipenem (MIC of 1 μg/ml). Both faropenem and imipenem had MICs of ≤4 μg/ml for all isolates of Bacteroides capillosus (10 isolates), Bacteroides splanchnicus (13 isolates), Bacteroides ureolyticus (11 isolates), Bilophila wadsworthia (11 isolates), Porphyromonas species (42 isolates), Prevotella species (78 isolates), Campylobacter species (25 isolates), Sutterella wadsworthensis (11 isolates), Fusobacterium nucleatum (19 isolates), Fusobacterium mortiferum/varium (20 isolates), and other Fusobacterium species (9 isolates). Faropenem and imipenem had MICs of 16 to 32 μg/ml for two strains of Clostridium difficile; the MICs for all other strains of Clostridium tested (69 isolates) were ≤4 μg/ml. Faropenem had MICs of 8 and 16 μg/ml, respectively, for two strains of Peptostreptococcus anaerobius (MICs of imipenem were 2 μg/ml). MICs were ≤4 μg/ml for all other strains of gram-positive anaerobic cocci (53 isolates) and non-spore-forming gram-positive rods (28 isolates). Other results were as expected and reported in previous studies. No metronidazole resistance was seen in gram-negative anaerobes other than S. wadsworthensis (18% resistant); 63% of gram-positive non-spore-forming rods were resistant. Some degree of clindamycin resistance was seen in most of the groups tested.

Resistance in anaerobic bacteria to all classes of antimicrobial agents is an increasing problem. β-Lactam resistance is generally due to the production of β-lactamases, and carbapenem resistance is generally due to metallo-β-lactamase enzymes that hydrolyze the antimicrobial agent (1, 3). Faropenem, a new oral penem antibiotic, is highly stable to a number of β-lactamases produced by clinical isolates. Faropenem had significant activity against the common respiratory pathogens Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis and poor activity against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Enterococcus faecium (18). This study was designed to evaluate the activity of faropenem, an oral penem antibiotic, against a wide range of clinically significant anaerobic bacteria.

The bacteria included in this study were recent clinical isolates from the Greater Los Angeles VA Healthcare Center. Bacteria were identified according to established procedures (5). MICs were determined by the NCCLS-approved Wadsworth agar dilution technique using 105 CFU/spot of inoculation and Brucella base-laked blood agar (6). Plates were incubated in an anaerobic chamber (Anaerobe Systems, San Jose, Calif.) for 48 h at 37°C. MICs were defined as described in the NCCLS protocol. Reference strains of Bacteroides fragilis (ATCC 25285) and Bacteroides thetaiotaomicron (ATCC 29741) were used as controls in each test. The following antimicrobial agents were obtained as powders: faropenem (Bayer Corporation, West Haven, Conn.), imipenem and cefoxitin (Merck, Rahway, N.J.), amoxicillin-clavulanate (GlaxoSmithKline, West Sussex, United Kingdom), and clindamycin and metronidazole (Sigma, St. Louis, Mo.).

The presence of the metallocarbapenemase gene cfiA was detected by PCR (16). An aliquot (2.5 μl) from a boiled, centrifuged lysate of each strain to be tested was added to a 47.5-μl reaction cocktail to give a final reaction mixture containing 1× Taq buffer B, 2.5 U of Taq DNA polymerase, 3.0 mM MgCl2, 0.2 mM deoxynucleoside triphosphates, 0.4 μM primer F677cfiA (5′-TGGGGTATGGTACCTTCCAA-3′), and 0.4 μM primer R1080cfiA (5′-AGCATACATCCGCCAAAAAG-3′). Reactions generating a band with a mobility of 403 bp indicated the presence of cfiA within the strain.

Table 1 lists the activity of faropenem compared to those of the other antimicrobial agents tested. For analytical purposes, the bacteria were grouped into species or genus groups of more than five isolates and the MIC ranges, MICs at which 50% of the isolates were inhibited (MIC50s), and MIC90s were reported (Table 1). The geometric mean was calculated when all values were within the range tested (i.e., no “greater than” values). As the breakpoint for faropenem has not yet been established, the percents susceptible, intermediate, and resistant were not reported for that agent. Overall, the MIC90 of faropenem (2 μg/ml) was twofold higher than the MIC90 of imipenem (1 μg/ml), as was the MIC50. However, in several groups of bacteria, this was not the case (see results below).

TABLE 1.

Activity of faropenem and comparative agents against anaerobic bacteria

Organism (no. of isolates) and antimicrobial agent MIC (μg/ml)a
Geometric mean %Sb %Ic %Rd
Range 50% 90%
Bacteroides fragilis group
    Bacteroides caccae (12)
        Faropenem 0.25-4 0.25 2 0.5
        Imipenem 0.12-2 0.25 1 0.3 100 0 0
        Amoxicillin-clavulanate 0.25-16 0.5 4 0.9 92 0 8
        Cefoxitin 4-32 16 32 15.1 67 33 0
        Clindamycin 0.25->32 2 >32 1.5 50 8 42
        Metronidazole 0.25-1 0.5 1 0.6 100 0 0
    Bacteroides distasonis/merdae group (19)
        Faropenem 1-4 2 2 1.9
        Imipenem 0.25-4 0.5 1 0.6 100 0 0
        Amoxicillin-clavulanate 2-16 4 4 3.7 90 5 5
        Cefoxitin 16-128 32 64 28.7 37 47 16
        Clindamycin 0.25->32 4 8 32 52 16
        Metronidazole 0.25-1 1 1 0.8 100 0 0
    Bacteroides fragilis (68)
        Faropenem 0.12-64 0.25 1 0.3
        Imipenem 0.12->32 0.12 2 0.2 97 0 3
        Amoxicillin-clavulanate 0.25-64 0.5 8 1 87 6 7
        Cefoxitin 4-128 16 32 14.0 80 13 7
        Clindamycin 0.12->32 1 >32 78 6 16
        Metronidazole 0.25-16 0.5 2 0.7 99 1 0
    Bacteroides ovatus (10)
        Faropenem 2-2 2 2 2
        Imipenem 0.25-0.50 0.25 0.5 0.3 100 0 0
        Amoxicillin-clavulanate 0.50-2 0.5 1 0.7 100 0 0
        Cefoxitin 16-32 32 32 26 30 70 0
        Clindamycin 0.50->32 2 >32 60 10 30
        Metronidazole 0.25-2 1 1 0.9 100 0 0
    Bacteroides stercoris (10)
        Faropenem 0.25-2 0.5 2 0.8
        Imipenem 0.12-8 0.5 0.5 0.5 90 10 0
        Amoxicillin-clavulanate 0.50-8 1 8 1.2 80 20 0
        Cefoxitin 2-64 32 32 13.9 40 50 10
        Clindamycin 0.12->32 2 4 70 20 10
        Metronidazole 0.25-2 1 2 0.9 100 0 0
    Bacteroides thetaiotaomicron (30)
        Faropenem 0.25-4 0.5 2 0.7
        Imipenem 0.12-2 0.5 0.5 0.4 100 0 0
        Amoxicillin-clavulanate 0.25-32 1 4 1.4 90 7 3
        Cefoxitin 2-64 32 64 20.6 33 37 30
        Clindamycin 0.12->32 2 >32 57 20 23
        Metronidazole 0.50-2 1 1 0.8 100 0 0
    Bacteroides uniformis (11)
        Faropenem 0.50-2 1 2 0.9
        Imipenem 0.25-2 0.5 1 0.5 100 0 0
        Amoxicillin-clavulanate 1-8 1 2 1.5 91 9 0
        Cefoxitin 4-64 16 32 15 55 36 9
        Clindamycin 0.12->32 2 >32 55 9 36
        Metronidazole 0.50-1 1 1 0.8 100 0 0
    Bacteroides vulgatus (16)
        Faropenem 1-8 2 4 2.1
        Imipenem 0.12-2 0.5 1 0.5 100 0 0
        Amoxicillin-clavulanate 0.50-16 1 16 2.4 63 12 25
        Cefoxitin 4-128 8 32 10.4 81 13 6
        Clindamycin 0.12->32 0.12 >32 75 0 25
        Metronidazole 0.25-2 0.25 0.5 0.4 100 0 0
Other Bacteroides species
    Bacteroides capillosus (10)
        Faropenem 0.12-1 0.12 1 0.2
        Imipenem 0.12-0.50 0.12 0.5 0.2 100 0 0
        Amoxicillin-clavulanate 0.12-0.50 0.25 0.5 0.3 100 0 0
        Cefoxitin 0.50-8 2 8 2.3 100 0 0
        Clindamycin 0.12->32 0.12 >32 80 0 20
        Metronidazole 0.25-4 0.5 0.5 0.5 100 0 0
    Bacteroides splanchnicus (13)
        Faropenem 0.25-0.50 0.5 0.5 0.4
        Imipenem 0.12-0.12 0.12 0.12 0.1 100 0 0
        Amoxicillin-clavulanate 0.12-0.50 0.5 0.5 0.4 100 0 0
        Cefoxitin 1-2 1 2 1.3 100 0 0
        Clindamycin 0.12->32 0.12 >32 85 0 15
        Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
    Bacteroides ureolyticus (11)
        Faropenem 0.12-0.50 0.12 0.12 0.1
        Imipenem 0.12-0.25 0.12 0.25 0.1 100 0 0
        Amoxicillin-clavulanate 0.12-0.5 0.12 0.12 0.1 100 0 0
        Cefoxitin 0.25-1.0 0.5 1 0.5 100 0 0
        Clindamycin 0.12->32 0.12 0.25 91 0 9
        Metronidazole 0.5-8 1 2 1.1 100 0 0
Bilophila wadsworthia (11)
    Faropenem 0.25-0.50 0.25 0.25 0.3
    Imipenem 0.25-0.50 0.5 0.5 0.4 100 0 0
    Amoxicillin-clavulanate 2-4 2 4 2.3 100 0 0
    Cefoxitin 8-128 16 64 21.9 64 18 18
    Clindamycin 0.12-0.25 0.12 0.25 0.1 100 0 0
    Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
Fusobacterium nucleatum (19)
    Faropenem 0.12-0.25 0.12 0.12 0.1
    Imipenem 0.12-0.25 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-4 0.12 0.5 0.2 100 0 0
    Cefoxitin 0.25-2 0.25 1 0.3 100 0 0
    Clindamycin 0.12-0.50 0.12 0.12 0.1 100 0 0
    Metronidazole 0.25-1 0.25 0.25 0.3 100 0 0
Fusobacterium mortiferum/varium group (20)
    Faropenem 0.12-2 0.5 1 0.4
    Imipenem 0.12-8 2 8 1.4 85 15 0
    Amoxicillin-clavulanate 0.12-8 1 4 1.4 90 10 0
    Cefoxitin 0.25-8 4 8 3.6 100 0 0
    Clindamycin 0.12-16 2 16 1.7 55 10 35
    Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
Fusobacterium necrophorum (9)
    Faropenem 0.12-0.12 0.1
    Imipenem 0.06-0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.12 0.1 100 0 0
    Cefoxitin 0.25-0.25 0.3 100 0 0
    Clindamycin 0.12-0.12 0.1 100 0 0
    Metronidazole 0.25-0.25 0.3 100 0 0
Porphyromonas asaccharolytica (12)
    Faropenem 0.12-0.12 0.12 0.12 0.1
    Imipenem 0.12-0.12 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.12 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.25-2 0.5 0.5 0.4 100 0 0
    Clindamycin 0.12->32 0.12 0.12 92 0 8
    Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
Porphyromonas endodontalis (10)
    Faropenem 0.12-0.50 0.12 0.12 0.1
    Imipenem 0.12-0.12 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.50 0.12 0.25 0.2 100 0 0
    Cefoxitin 0.25-1 0.25 0.5 0.3 100 0 0
    Clindamycin 0.12->32 0.12 32 80 0 20
    Metronidazole 0.25-1 0.25 0.5 0.3 100 0 0
Porphyromonas gingivalis (10)
    Faropenem 0.12-0.12 0.12 0.12 0.1
    Imipenem 0.12-0.12 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.12 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.25-0.50 0.25 0.25 0.3 100 0 0
    Clindamycin 0.12-0.12 0.12 0.12 0.1 100 0 0
    Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
Porphyromonas levii-like organisms (10)
    Faropenem 0.12-4 0.12 1 0.2
    Imipenem 0.12-2 0.12 0.5 0.2 100 0 0
    Amoxicillin-clavulanate 0.12-4 0.12 0.5 0.2 100 0 0
    Cefoxitin 0.25-16 0.25 4 0.7 100 0 0
    Clindamycin 0.12->32 0.12 2 90 0 10
    Metronidazole 0.25-1 0.5 1 0.5 100 0 0
Prevotella bivia (11)
    Faropenem 0.12-2 0.25 0.5 0.3
    Imipenem 0.06-0.50 0.12 0.5 0.2 100 0 0
    Amoxicillin-clavulanate 0.12-2 0.12 0.5 0.2 100 0 0
    Cefoxitin 0.25-16 1 2 0.8 100 0 0
    Clindamycin 0.12->32 0.12 >32 64 0 36
    Metronidazole 0.25-16 1 2 1.3 91 9 0
Prevotella oris/buccae group (19)
    Faropenem 0.12-4 0.12 1 0.2
    Imipenem 0.12-0.5 0.12 0.25 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-2 0.12 2 0.3 100 0 0
    Cefoxitin 0.25-16 2 16 2.3 100 0 0
    Clindamycin 0.12->32 0.12 0.12 95 0 5
    Metronidazole 0.25-1 0.25 0.5 0.4 100 0 0
Prevotella disiens (12)
    Faropenem 0.12-2 0.12 0.5 0.2
    Imipenem 0.12-1 0.12 0.5 0.2 100 0 0
    Amoxicillin-clavulanate 0.12-8 0.25 4 0.3 92 8 0
    Cefoxitin 0.25-16 0.25 8 1 100 0 0
    Clindamycin 0.12-2 0.12 0.12 0.2 100 0 0
    Metronidazole 0.25-2 1 2 0.7 100 0 0
Other Prevotella species (36)e
    Faropenem 0.12-2 0.12 0.5 0.2
    Imipenem 0.06-0.5 0.12 0.25 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-4 0.12 2 0.3 100 0 0
    Cefoxitin 0.25-16 0.5 16 1.1 100 0 0
    Clindamycin 0.12->32 0.12 0.12 91 0 9
    Metronidazole 0.25-16 0.25 1 0.5 97 3 0
Sutterella wadsworthensis (11)
    Faropenem 0.12-2 0.25 0.5 0.3
    Imipenem 0.25-1 0.25 1 0.4 100 0 0
    Amoxicillin-clavulanate 0.50-2 0.5 2 0.7 100 0 0
    Cefoxitin 0.50-16 1 4 1.3 100 0 0
    Clindamycin 0.12-8 4 8 2.9 36 19 45
    Metronidazole 0.25-128 2 64 2.9 82 0 18
Campylobacter species (25)f
    Faropenem 0.12-0.25 0.12 0.25 0.1
    Imipenem 0.12-0.50 0.25 0.5 0.3 100 0 0
    Amoxicillin-clavulanate 0.12-0.12 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.25-8 0.50 4 0.9 100 0 0
    Clindamycin 0.12-4 0.25 2 0.3 96 4 0
    Metronidazole 0.25-2 1 2 0.8 100 0 0
Clostridium difficile (11)
    Faropenem 0.50-32 8 16 6.6
    Imipenem 0.50-16 4 16 4.8 64 18 18
    Amoxicillin-clavulanate 0.12-2 1 2 0.7 100 0 0
    Cefoxitin 1->128 >64 >128 9 27 64
    Clindamycin 1->32 >32 >32 27 9 64
    Metronidazole 0.25-1 0.25 1 0.3 100 0 0
Clostridium perfringens (20)
    Faropenem 0.12-1 0.5 0.5 0.4
    Imipenem 0.06-0.50 0.12 0.25 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-1 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.25-2 1 2 0.9 100 0 0
    Clindamycin 0.12-2 0.5 2 0.4 100 0 0
    Metronidazole 0.25-1 0.5 1 0.6 100 0 0
Clostridium ramosum (10)
    Faropenem 0.12-1 0.25 1 0.3
    Imipenem 0.25-1 0.25 0.5 0.3 100 0 0
    Amoxicillin-clavulanate 0.12-1 0.12 0.25 0.2 100 0 0
    Cefoxitin 4-64 8 64 14.9 60 10 30
    Clindamycin 0.12-4 2 4 1.9 50 50 0
    Metronidazole 0.50->128 0.5 1 90 0 10
Clostridium sordellii (10)
    Faropenem 0.12-0.50 0.12 0.12 0.1
    Imipenem 0.12-0.25 0.12 0.25 0.2 100 0 0
    Amoxicillin-clavulanate 0.12-0.25 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.25-8 0.25 0.5 0.4 100 0 0
    Clindamycin 0.25->32 1 1 90 0 10
    Metronidazole 0.25-1 1 1 0.7 100 0 0
Clostridium sporogenes (10)
    Faropenem 0.50-1 1 1 0.9
    Imipenem 0.12-0.50 0.25 0.5 0.3 100 0 0
    Amoxicillin-clavulanate 0.12-0.50 0.25 0.5 0.3 100 0 0
    Cefoxitin 0.25-1 0.5 1 0.5 100 0 0
    Clindamycin 0.25-32 16 16 8 20 0 80
    Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
Other Clostridium species (10)g
    Faropenem 0.50-8 2 8 2.3
    Imipenem 0.25-4 1 2 0.8 100 0 0
    Amoxicillin-clavulanate 0.25-8 0.5 2 0.6 90 10 0
    Cefoxitin 1-64 8 64 10.6 70 10 20
    Clindamycin 0.12->32 1 >32 80 0 20
    Metronidazole 0.25-8 0.5 1 0.6 100 0 0
Peptoniphilus asaccharolyticus (formerly     Peptostreptococcus asaccharolyticus) (10)
    Faropenem 0.12-2 0.12 1 0.2
    Imipenem 0.12-0.12 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.50 0.12 0.25 0.1 100 0 0
    Cefoxitin 0.25-2 0.25 1 0.4 100 0 0
    Clindamycin 0.12->32 0.12 >32 60 20 20
    Metronidazole 0.50-2 1 1 0.9 100 0 0
Finegoldia magna (formerly Peptostreptococcus     magnus) (10)
    Faropenem 0.12-1 0.25 0.25 0.2
    Imipenem 0.06-0.12 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.50 0.12 0.25 0.2 100 0 0
    Cefoxitin 0.25-8 0.5 1 0.6 100 0 0
    Clindamycin 0.12->32 0.5 4 0.4 80 10 10
    Metronidazole 0.25-2 0.25 0.5 0.4 100 0 0
Micromonas micros (formerly Peptostreptococcus     micros) (12)
    Faropenem 0.12-0.12 0.12 0.12 0.1
    Imipenem 0.12-0.12 0.12 0.12 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-0.12 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.50-2 1 2 0.9 100 0 0
    Clindamycin 0.12-1 0.12 0.25 0.2 100 0 0
    Metronidazole 0.25-0.25 0.25 0.25 0.3 100 0 0
Anaerococcus prevotii/tetradius group (formerly     Peptostreptococcus prevotii/tetradius) (10)
    Faropenem 0.12-4 0.12 2 0.2
    Imipenem 0.06-0.50 0.12 0.5 0.1 100 0 0
    Amoxicillin-clavulanate 0.12-1 0.12 0.12 0.1 100 0 0
    Cefoxitin 0.25-4 0.25 0.5 0.4 100 0 0
    Clindamycin 0.12-1 0.12 0.5 0.2 100 0 0
    Metronidazole 0.25->128 0.5 2 90 0 10
Other gram-positive anaerobic cocci (13)h
    Faropenem 0.12-16 0.5 8 0.5
    Imipenem 0.12-2 0.12 2 0.3 100 0 0
    Amoxicillin-clavulanate 0.12-32 0.25 4 0.5 93 0 7
    Cefoxitin 0.12-16 8 16 3.2 100 0 0
    Clindamycin 0.12-0.50 0.25 0.5 0.2 100 0 0
    Metronidazole 0.25->128 1 128 71 0 29
Gram-positive rods (non-spore-forming) (28)i
    Faropenem 0.12-2 0.12 0.5 0.2
    Imipenem 0.06-0.50 0.12 0.25 0.2 100 0 0
    Amoxicillin-clavulanate 0.12-0.50 0.12 0.5 0.2 100 0 0
    Cefoxitin 0.12-32 0.25 8 0.7 93 7 0
    Clindamycin 0.12->32 0.25 >32 0.3 82 0 18
    Metronidazole 0.25->128 32 >128 5.8 28 8 64
All organisms (579)
    Faropenem 0.12-64 0.25 2 0.4
    Imipenem 0.06->32 0.12 1 0.2 98 1 1
    Amoxicillin-clavulanate 0.12-64 0.25 4 0.4 95 3 2
    Cefoxitin 0.12->128 2 32 2.5 84 10 6
    Clindamycin 0.12->32 0.25 >32 0.4 77 7 16
    Metronidazole 0.25->128 0.5 2 0.6 94 1 5
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a

50%, MIC50; 90%, MIC90.

b

%S, percent susceptible. Susceptible category breakpoints: amoxicillin-clavulanate, 4 μg/ml; cefoxitin, 16 μg/ml; clindamycin, 2 μg/ml; imipenem, 2 μg/ml; metronidazole, 8 μg/ml; faropenem, not yet established.

c

%I, percent intermediate.

d

%R, percent resistant.

e

Prevotella corporis (three), Prevotella enoeca (three), Prevotella heparinolytica (one), Prevotella intermedia/nigrescens (seven), Prevotella loescheii (three), Prevotella melaninogenica/denticola (eight), Prevotella oris (nine), Prevotella zoogleoformans (two), Prevotella zoogleoformans/heparinolytica (two).

f

Campylobacter concisus (three), Campylobacter curvus (eight), Campylobacter gracilis (five), Campylobacter rectus (five), other Campylobacter species (four).

g

Clostridium butyricum (three), Clostridium clostridioforme (four), Clostridium innocuum (three).

h

Peptostreptococcus anaerobius (nine), Streptococcus intermedius (four).

i

Actinomyces israelii (three), Actinomyces naeslundii (three), Actinomyces odontolyticus (two), Actinomyces viscosus (five), Eggerthella lenta (three), Eubacterium limosum (three), Atopobium minutum (two), Propionibacterium acnes (four), Propionibacterium propionicus (three).

Sixty-eight strains of B. fragilis were tested for the presence of the cfiA gene by PCR. Eight of the B. fragilis isolates possessed the cfiA gene. Faropenem and imipenem had MICs of 64 and >32 μg/ml, respectively, for two of these strains (these isolates were also highly resistant to amoxicillin-clavulanic acid and cefoxitin). These two isolates were from the same patient, although from separate specimens; nevertheless, they may represent a single strain. Two strains had faropenem MICs of 2 μg/ml (one of these strains also had an imipenem MIC of 2 μg/ml, and the other had an MIC of 0.5 μg/ml). The other four strains had faropenem MICs of 0.25 to 0.5 μg/ml (two of these strains had imipenem MICs of 2 μg/ml, and a third had an MIC of 1 μg/ml).

In B. fragilis, high-level carbapenem resistance is mediated by the cfiA gene and requires an upstream insertion sequence (IS) element. Several such elements have thus far been identified: IS1186 (10), IS1187 and IS1188 (11), and IS942 (13). Other studies have also described strains that have the cfiA gene yet do not have high-level penem resistance and have shown that these strains do not have the IS element, which is associated with high-level cfiA expression (4). Additional studies to determine whether the cfiA-positive strains identified in this study have upstream ISs are under way.

Three additional strains for which faropenem had intermediate MICs did not have the cfiA gene. Faropenem had an MIC of 16 μg/ml for an additional isolate of B. fragilis. This strain was sensitive to imipenem (MIC of 1 μg/ml). Faropenem had MICs of 8 μg/ml for two additional isolates of B. fragilis (MICs of imipenem were 4 and 2 μg/ml for these isolates). The MICs of these strains were reconfirmed by repeat testing. These strains all had the cepA β-lactamase gene, but the CepA β-lactamase is not active against carbapenems. The mechanism of this intermediate carbapenem resistance is not yet known. In other species, synergy between efflux pumps and the permeability barrier may contribute to penem resistance (7) and may affect penem resistance selectively. For example, changes in a specific porin may affect imipenem but not other penems (8, 9; T. Kohler, C. Cherbuliez, and J. C. Pechere, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1519, p. 98, 2001). Also, efflux pumps in P. aeruginosa, for example, have preferences for certain penem substrates (J. Kohler, K. Young, R. E. Painter, J. A. Inumerable, and L. L. Silver, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1518, p. 97, 2001). Such mechanisms have not yet been described for B. fragilis.

One strain each of Porphyromonas endodontalis, Porphyromonas asaccharolytica, and Porphyromonas levii was clindamycin resistant. Four strains of Prevotella bivia and four strains of Prevotella species were clindamycin resistant. All other strains of Porphyromonas and Prevotella species were susceptible to all of the agents tested.

Bilophila wadsworthia was the third most common anaerobe isolated (after the B. fragilis group and Peptostreptococcus species) in cases of perforated or gangrenous appendicitis (2) and was found in nearly one-half of all specimens. MICs of both faropenem and imipenem were ≤0.5 μg/ml for all of the strains tested. All strains of Bilophila were susceptible to the other agents except for two strains that were resistant to cefoxitin. Sutterella wadsworthensis, a gram-negative anaerobic rod described in 1996 (17), was found in more than 10% of intra-abdominal specimens. The penems had MICs of ≤2 μg/ml for Sutterella species. Four strains of Sutterella were resistant to clindamycin, and two strains were resistant to metronidazole. All of the strains of Fusobacterium nucleatum, Fusobacterium mortiferum/varium, and other Fusobacterium species were sensitive to all agents except for seven strains of the F. mortiferum/varium group which were resistant to clindamycin. For several of the gram-negative rods tested, both the geometric mean and MIC90 of faropenem were lower than the corresponding values of imipenem (B. wadsworthia, S. wadsworthensis, and Campylobacter species). The geometric mean MIC and MIC90 for F. mortiferum/varium was threefold lower for faropenem than for imipenem (1 and 8 μg/ml, respectively); similarly, the geometric mean MIC was lower (0.4 and 1.4 μg/ml, respectively).

Faropenem had MICs of 16 and 32 μg/ml, respectively, for two strains of Clostridium difficile; these strains were also imipenem resistant. Faropenem had MICs of 8 μg/ml for two strains of Clostridium innocuum, for which imipenem MICs were 1 to 2 μg/ml. Faropenem had MICs of ≤4 μg/ml for all other strains of Clostridium tested.

Faropenem had an MIC of 8 μg/ml for one strain and MICs of 16 μg/ml for one strain of Peptostreptococcus anaerobius (MICs of imipenem were 1 to 2 μg/ml). These strains also had elevated MICs of amoxicillin-clavulanate (2 to 32 μg/ml versus the mean MIC of 0.5 μg/ml) and cefoxitin (8 to 16 μg/ml versus the mean MIC of 3.2 μg/ml). There are no descriptions of resistance mechanisms for Peptostreptococcus species that would account for these results. Faropenem and imipenem had MICs of <4 μg/ml for all other strains of gram-positive anaerobic cocci (55 isolates) and for all strains of non-spore-forming gram-positive rods (27 isolates).

There is limited information about the activity of faropenem against anaerobes (14). Spangler et al. studied the activity of WY-49605 (an earlier designation for faropenem) against anaerobes and found no B. fragilis group isolates with MICs of >4 μg/ml (the MIC90s for B. fragilis group isolates were 1 to 4 μg/ml, depending on the species) (15). Woodcock et al. reported an MIC90 of 4 μg/ml for 24 strains of B. fragilis; the MIC range extended to 32 μg/ml (18). No strains of resistant Peptostreptococcus (19 strains tested) were seen in that study. Strains of C. difficile with moderately high MICs have been found (MIC50 of 4 μg/ml and MIC90 of 8 μg/ml [15, 18]). MICs for Peptostreptococcus were ≤2 μg/ml, and the MIC90 was 1 μg/ml (15).

Faropenem is stable to many β-lactamases, including TEM-1, SHV-1, TEM-3, and TEM-9 (18). β-Lactamases belonging to Class-group 2f, including Imi-I from Enterobacter cloacae, hydrolyze penems and carbapenems at modest rates (12). This class of β-lactamase has not been reported in Bacteroides. Both penems and carbapenems are also degraded by the metallo-β-lactamases coded for by the cfiA gene (1, 19). Imipenem resistance in anaerobes is most often attributable to degradation by this enzyme, but there may be other mechanisms that are also important (3). In aerobes, both efflux pumps and permeability barriers contribute to carbapenem resistance (7). These mechanisms have not yet been described in anaerobes.

Faropenem is a promising novel oral penem agent with very good activity against a wide range of gram-negative and gram-positive anaerobic bacteria. Efficacy will need to be confirmed in clinical trials.

Acknowledgments

This study was funded in part by VA Merit Review funds and in part by Bayer Corporation.

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