The in vitro activities of LFF571, a novel analog of GE2270A that inhibits bacterial growth by binding with high affinity for protein synthesis elongation factor Tu, fidaxomicin, and 10 other antimicrobial agents were determined against 50 strains of Clostridium difficile and 630 other anaerobic and aerobic organisms of intestinal origin. LFF571 possesses potent activity against C. difficile and most other Gram-positive anaerobes (MIC90, ≤0.25 μg/ml), with the exception of bifidobacteria and lactobacilli. The MIC90s for aerobes, including enterococci, Staphylococcus aureus (as well as methicillin-resistant S. aureus [MRSA] isolates), Streptococcus pyogenes, and other streptococci were 0.06, 0.125, 2, and 8 μg/ml, respectively. Comparatively, fidaxomicin showed variable activity against Gram-positive organisms: MIC90s against C. difficile, Clostridium perfringens, and Bifidobacterium spp. were 0.5, ≤0.015, and 0.125 μg/ml, respectively, but >32 μg/ml against Clostridium ramosum and Clostridium innocuum. MIC90 for S. pyogenes and other streptococci was 16 and >32 μg/ml, respectively. LFF571 and fidaxomicin were generally less active against Gram-negative anaerobes.

TD-1792 is a multivalent glycopeptide-cephalosporin heterodimer antibiotic with potent activity against Gram-positive bacteria. We tested TD-1792 against 377 anaerobes and 34 strains of Corynebacterium species. Against nearly all Gram-positive strains, TD-1792 had an MIC90 of 0.25 μg/ml and was typically 3 to 7 dilutions more active than vancomycin and daptomycin.

The comparative in vitro activities of ABT-773 against 207 aerobic and 162 anaerobic antral sinus puncture isolates showed that erythromycin-resistant pneumococcal strains were susceptible to ABT-773 (≤0.125 μg/ml); the MIC at which 90% of the isolates tested were inhibited for Haemophilus influenzae and other Haemophilus spp. was 4 μg/ml; and all Moraxella spp. and beta-lactamase-producing Prevotella species strains were inhibited by ≤0.125 μg/ml. Among the anaerobes tested, only fusobacteria (45%) required ≥4 μg of ABT-773/ml for inhibition. ABT-773 may offer a therapeutic alternative for sinus infections.

GAR-936 is a new semisynthetic glycylcycline with a broad antibacterial spectrum, including tetracycline-resistant strains. The in vitro activities of GAR-936, minocycline, doxycycline, tetracycline, moxifloxacin, penicillin G, and erythromycin were determined by agar dilution methods against 268 aerobic and 148 anaerobic strains of bacteria (including Pasteurella, Eikenella, Moraxella, Bergeyella, Neisseria, EF-4, Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Staphylococcus, Streptococcus, Enterococcus, Corynebacterium, Propionibacterium, Peptostreptococcus, and Actinomyces) isolated from infected human and animal bite wounds in humans, including strains resistant to commonly used antimicrobials. GAR-936 was very active, with an MIC at which 90% of the strains are inhibited (MIC90) of ≤0.25 μg/ml, against all aerobic gram-positive and -negative strains, including tetracycline-resistant strains of Enterococcus, Streptococcus, and coagulase-negative staphylococci, except for Eikenella corrodens (MIC90, ≤4 μg/ml). GAR-936 was also very active against all anaerobic species, including tetracycline-, doxycycline-, and minocycline-resistant strains of Prevotella spp., Porphyromonas spp., Bacteroides tectum, and Peptostreptococcus spp., with an MIC90 of ≤0.25 μg/ml. Erythromycin- and moxifloxacin-resistant fusobacteria were susceptible to GAR-936, with an MIC90 of 0.06 μg/ml.

We studied the comparative in vitro activities of ABT-773, a new ketolide, against 268 aerobic and 148 anaerobic recent isolates from clinical bites using an agar dilution method and inocula of 104 CFU/spot for aerobes and 105 CFU for anaerobes. The following are the MIC ranges and MICs at which 90% of isolates are inhibited (MIC90s) of ABT-773 for various isolates, respectively: Pasteurella multocida and Pasteurella septica, 0.125 to 2 and 1 μg/ml; other Pasteurella species, 0.125 to 1 and 0.5 μg/ml; Corynebacterium spp., 0.015 to 0.06 and 0.015 μg/ml; Staphylococcus aureus, 0.03 to 0.06 and 0.06 μg/ml; coagulase-negative staphylococci, 0.015 to >32 and 32 μg/ml; streptococci, 0.015 to 0.03 and 0.03 μg/ml; Eikenella corrodens, 0.25 to 1 and 1 μg/ml; and Bergeyella zoohelcum, 0.03 to 0.25 and 0.06 μg/ml. For anaerobes the MIC ranges and MIC90s of ABT-773 were as follows, respectively: Prevotella heparinolytica, 0.06 to 0.125 and 0.125 μg/ml; Prevotella spp., 0.015 to 0.125 and 0.06 μg/ml; Porphyromonas spp., 0.015 to 0.03 and 0.015 μg/ml; Fusobacterium nucleatum, 0.5 to 8 and 8 μg/ml; other Fusobacterium spp., 0.015 to 8 and 0.5 μg/ml; Bacteroides tectum, 0.015 to 0.5 and 0.06 μg/ml; and Peptostreptococcus spp., 0.015 to 0.25 and 0.03 μg/ml. ABT-773 was more active than all macrolides tested against S. aureus, E. corrodens, and anaerobes, but all compounds were poorly active against F. nucleatum. The activity of ABT-773 was within 1 dilution of that of azithromycin against Pasteurella spp., and ABT-773 was four- to eightfold more active than clarithromycin against Pasteurella spp. ABT-773 may offer a therapeutic alternative for bite wound infections.

By using an agar dilution method, the comparative in vitro activities of ertapenem (MK-0826) were studied against 1,001 anaerobes isolated from human intra-abdominal infections in 17 countries worldwide. MK-0826 was uniformly active against all isolates, including all Bacteroides fragilis group species isolates, with the exception of 12 of 61 (20%) strains of Bilophila wadsworthia, 3 strains of lactobacilli, and 1 isolate of Acidaminococcus fermentans. Geographical variation in activity was not observed.

The comparative activity of telithromycin (HMR 3647) against 419 human anaerobic isolates was determined by the agar dilution method. At concentrations of ≤0.5 μg/ml, telithromycin was active against Actinomyces israelii, Actinomyces odontolyticus, Bacteroides tectum, Bacteroides ureolyticus, Bacteroides gracilis (now Campylobacter gracilis), Porphyromonas spp. (including Porphyromonas gingivalis and Porphyromonas macacae), Prevotella intermedia, Prevotella heparinolytica, and almost all Peptostreptococcus species. Clostridia showed species and strain variability, often with a biphasic pattern. Fusobacterium species, except Fusobacterium russii, were relatively resistant.

The activities of gemifloxacin (SB 265805, LB20304) and comparator agents were determined by an agar dilution method against 419 clinical strains of less-commonly identified species of anaerobes. Gemifloxacin was generally more active than trovafloxacin against gram-positive strains by one to two dilutions. Peptostreptococci (Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus micros, and Peptostreptococcus prevotii) and Porphyromonas spp. (Porphyromonas asaccharolytica, Porphyromonas canoris, Porphyromonas gingivalis, and Porphyromonas macacae) were all susceptible to ≤0.25 μg of gemifloxacin per ml. The MICs of gemifloxacin at which 90% of the following strains were inhibited (MIC90s) were ≤2 μg/ml: Actinomyces israelii, Actinomyces odontolyticus, Clostridium innocuum, Clostridium clostridioforme, Anaerobiospirillum spp., Bacteroides tectum, Bacteroides ureolyticus, Bacteroides gracilis (now Campylobacter gracilis), Prevotella intermedia, Prevotella heparinolytica, and the Prevotella oris-buccae group. Fusobacterium naviforme and Fusobacterium necrophorum were also susceptible to ≤2 μg of gemifloxacin per ml, while Fusobacterium varium strains exhibited a bimodal pattern; the other Fusobacterium species, such as Fusobacterium ulcerans and Fusobacterium russii, as well as Veillonella spp., the Prevotella melaninogenica group, Prevotella bivia, Clostridium difficile, and Bilophila wadsworthia were relatively resistant to gemifloxacin (MIC90s, ≥4 μg/ml).

Gemifloxacin mesylate (SB 265805), a new fluoronaphthyridone, was tested against 359 recent clinical anaerobic isolates by the National Committee for Clinical Laboratory Standards reference agar dilution method with supplemented brucella blood agar and an inoculum of 105 CFU/spot. Comparative antimicrobials tested included trovafloxacin, levofloxacin, grepafloxacin, sparfloxacin, sitafloxacin (DU-6859a), penicillin G, amoxicillin clavulanate, imipenem, cefoxitin, clindamycin, and metronidazole. The MIC50 and MIC90 (MICs at which 50 and 90% of the isolates were inhibited) of gemifloxacin against various organisms (with the number of strains tested in parentheses) were as follows (in micrograms per milliliter): for Bacteroides fragilis (28), 0.5 and 2; for Bacteroides thetaiotaomicron (24), 1 and 16; for Bacteroides caccae (12), 1 and 16; for Bacteroides distasonis (12), 8 and >16; for Bacteroides ovatus (12), 4 and >16; for Bacteroides stercoris (12), 0.5 and 0.5; for Bacteroides uniformis (12), 1 and 4; for Bacteroides vulgatus (11), 4 and 4; for Clostridium clostridioforme (15), 0.5 and 0.5; for Clostridium difficile (15), 1 and >16; for Clostridium innocuum (13), 0.125 and 2; for Clostridium perfringens (13), 0.06 and 0.06; for Clostridium ramosum (14), 0.25 and 8; for Fusobacterium nucleatum (12), 0.125 and 0.25; for Fusobacterium necrophorum (11), 0.25 and 0.5; for Fusobacterium varium (13), 0.5 and 1; for Fusobacterium spp. (12), 1 and 2; for Peptostreptococcus anaerobius (13), 0.06 and 0.06; for Peptostreptococcus asaccharolyticus (13), 0.125 and 0.125; for Peptostreptococcus magnus (14), 0.03 and 0.03; for Peptostreptococcus micros (12), 0.06 and 0.06; for Peptostreptococcus prevotii (14), 0.06 and 0.25; for Porphyromonas asaccharolytica (11), 0.125 and 0.125; for Prevotella bivia (10), 8 and 16; for Prevotella buccae (10), 2 and 2; for Prevotella intermedia (10), 0.5 and 0.5; and for Prevotella melaninogenica (11), 1 and 1. Gemifloxacin mesylate (SB 265805) was 1 to 4 dilutions more active than trovafloxacin against fusobacteria and peptostreptococci, and the two drugs were equivalent against clostridia and P. asaccharolytica. Gemifloxacin was equivalent to sitafloxacin (DU 6859a) against peptostreptococci, C. perfringens, and C. ramosum, and sitafloxacin was 2 to 3 dilutions more active against fusobacteria. Sparfloxacin, grepafloxacin, and levofloxacin were generally less active than gemifloxacin against all anaerobes.

The activity of gatifloxacin against 308 aerobes and 112 anaerobes isolated from bite wound infections was studied. Gatifloxacin was active at ≤0.016 μg/ml against all 148 Pasteurella isolates (eight species and three subspecies) tested and all other aerobes tested, including Actinobacillus-Haemophilus spp., Eikenella corrodens, Neisseria weaveri, Weeksella zoohelcum, staphylococci, and streptococci. Fusobacteria were sometimes resistant. Gatifloxacin MICs at which 90% of the isolates were inhibited were 0.125 μg/ml against Bacteroides tectum and Prevotella spp., 0.25 μg/ml against Porphyromonas spp., and 0.5 μg/ml against peptostreptococci.

Linezolid was tested against 420 aerobes and anaerobes, including 148 Pasteurella isolates, by an agar dilution method. Linezolid was active against all Pasteurella multocida subsp. multocida and P. multocida subsp. septica isolates and most Pasteurella canis, Pasteurella dagmatis, and Pasteurella stomatis isolates. The MIC was ≤2 μg/ml for staphylococci, streptococci, EF-4b, Weeksella zoohelcum, Fusobacterium nucleatum, other fusobacteria, Porphyromonas spp., Prevotella spp., peptostreptococci, and almost all Bacteroides tectum isolates.

By an agar dilution method, the antimicrobial susceptibilities of antral sinus puncture isolates were studied. Pneumococci were generally susceptible to amoxicillin, azithromycin, and clarithromycin, but 17% of pneumococcal isolates were resistant to cefuroxime. Haemophilus influenzae isolates were resistant to amoxicillin and clarithromycin. β-Lactamase production occurred in 69% of Prevotella species. One-third of Peptostreptococcus magnus isolates were resistant to azithromycin and clarithromycin. Cefuroxime had limited activity against Prevotella species and P. magnus. Levofloxacin was active against most isolates except peptostreptococci. Amoxicillin-clavulanate was active against all isolates, with the MIC at which 90% of the isolates were inhibited being ≤1 μg/ml.

The activities of HMR 3004 and HMR 3647 and comparator agents, especially macrolides, were determined by the agar dilution method against 262 aerobic and 120 anaerobic strains isolated from skin and soft tissue infections associated with human and animal bite wounds. HMR 3004 and HMR 3647 were active against almost all aerobic and fastidious facultative isolates (MIC at which 90% of the isolates are inhibited [MIC90], ≤0.5 and 1 μg/ml, respectively) and against all anaerobes [Bacteroides tectum, Porphyromonas macacae (salivosa), Prevotella heparinolytica, Porphyromonas sp., Prevotella sp., and peptostreptococci] at ≤0.25 and ≤0.5 μg/ml, respectively, except Fusobacterium nucleatum (HMR 3004, MIC90 = 16 μg/ml; HMR 3647, MIC90 = 8 μg/ml) and other Fusobacterium species (MIC90, 1 and 2 μg/ml, respectively). In general, HMR 3004 and HMR 3647 were more active than any of the macrolides tested. Azithromycin was more active than clarithromycin against all Pasteurella species, including Pasteurella multocida subsp. multocida, Eikenella corrodens, and Fusobacterium species, while clarithromycin was more active than azithromycin against Corynebacterium species, Weeksella zoohelcum, B. tectum, and P. heparinolytica.

MICs of CB-183,315, a novel lipopeptide antibiotic, vancomycin, and metronidazole were determined for intestinal anaerobes and Enterobacteriaceae. The MIC90s for Gram-negative anaerobes were >8,192, 8,192, and 4 μg/ml for CB-183,315, vancomycin, and metronidazole, respectively. Against Enterobacteriaceae, the MIC90s were >8,192 μg/ml, 1,024 μg/ml, and 1,024 μg/ml, respectively. The CB-183,315 MIC90 for Clostridium difficile was 0.5 μg/ml. Its lack of activity against normal fecal organisms makes it a promising new agent for treating C. difficile.

A 10-day course of oral fidaxomicin (200 mg twice a day [b.i.d.]), a potent new macrocyclic drug, was compared to vancomycin (125 mg four times a day [q.i.d.]) in 1,164 adults (1,105 in the modified intent-to-treat [mITT] population) with Clostridium difficile infection in two phase III randomized, double-blind trials at sites in North America and 7 European countries. Of 1,105 mITT patients, 792 (71.7%), including 719/999 (72.0%) in the per-protocol (PP) population, provided a C. difficile strain at baseline, of whom 356 received fidaxomicin with 330 cures (92.7%) and 363 received vancomycin with 329 cures (90.6%). The susceptibilities (MIC90) of baseline isolates did not predict clinical cure, failure, or recurrence for fidaxomicin (MIC90, 0.25 μg/ml for both; range, ≤0.007 to 1 μg/ml), but there was a one-dilution difference in the MIC90 (but not the MIC50) for vancomycin (MIC90, 2 μg/ml [range, 0.25 to 8 μg/ml] for cure and 4.0 μg/ml [range, 0.5 to 4 μg/ml] for failures). A total of 65 (7.9%) “rifaximin-resistant” (MIC > 256 μg/ml) strains were isolated in both treatment groups on enrollment, which increased to 25% for failures at the end of therapy. No resistance to either fidaxomicin or vancomycin developed during treatment in either of the phase III studies, although a single strain isolated from a cured patient had an elevated fidaxomicin MIC of 16 μg/ml at the time of recurrence. All isolates were susceptible to ≤4 μg/ml of metronidazole. When analyzed by restriction endonuclease analysis (REA) type, 247/719 (34.4%) isolates were BI group isolates, and the MICs were generally higher for all four drugs tested (MIC90s: fidaxomicin, 0.5; vancomycin, 2.0; metronidazole, 2.0; and rifaximin, >256 μg/ml) than for the other REA types. There was no correlation between the MIC of a baseline clinical isolate and clinical outcome. MIC90s were generally low for fidaxomicin and vancomycin, but BI isolates had higher MICs than other REA group isolates.

NXL104, a novel β-lactamase inhibitor, was tested at a constant concentration of 4 μg/ml in combination with ceftazidime (CAZ), with and without added metronidazole, against 396 β-lactamase-producing strains of anaerobic bacteria. MIC50/MIC90 values for Bacteroides fragilis and the B. fragilis group were 8/16 and 64/>128 μg/ml, respectively. Although CAZ-NXL104 had limited activity against most anaerobic strains, in combination with metronidazole it shows potential for treating mixed infections involving resistant Enterobacteriaceae and anaerobes.

After ertapenem was added to the formulary of a 344-bed community teaching hospital, we retrospectively studied its effect on antimicrobial utilization and on the in vitro susceptibility of various antimicrobial agents against Pseudomonas aeruginosa. Three study periods were defined as preintroduction (months 1 to 9), postintroduction but before the autosubstitution of ertapenem for ampicillin-sulbactam (months 10 to 18), and after the policy of autosubstitution (months 19 to 48) was initiated. Ertapenem usage rose slowly from introduction to a range of 36 to 48 defined daily doses/1,000 patient days (DDD) with a resultant decrease in ampicillin-sulbactam usage due to autosubstitution. Imipenem usage peaked 6 months after the introduction of ertapenem and started to decline coincidently with the increased use of ertapenem. During the second period, imipenem usage decreased (slope = −1.28; P = 0.002). Prior to the introduction of ertapenem, the susceptibility of P. aeruginosa to imipenem increased from 61 to 81% at month 7 but then decreased slightly to 67% at month 9. After the introduction of ertapenem, susceptibility continued to increase; the increasing trend was significant (slope = 1.74; P < 0.001). In the third period, the median susceptibility (interquartile range) was 88% (82 to 95%). This change appeared related to decreased imipenem usage. For every unit decrease in the monthly DDD of imipenem, there was an increase of 0.38% (P = 0.008) in the susceptibility of P. aeruginosa to imipenem in the same month. Ertapenem was effective in our antimicrobial stewardship program and may have helped improve the P. aeruginosa antimicrobial susceptibility to imipenem by decreasing the unnecessary usage and selective pressure of antipseudomonal agents.

Against 182 anaerobe and 241 aerobe strains obtained from diabetic foot infections, doripenem was the most active carbapenem against Pseudomonas aeruginosa (MIC90, 2 μg/ml), more active than imipenem against Proteus mirabilis, and ertapenem was more active against Escherichia coli and Klebsiella spp. The MIC50 and MIC90 values were ≤0.125 μg/ml for methicillin-sensitive Staphylococcus aureus and all streptococci and 0.25/1 for Bacteroides fragilis.

Against 443 aerobic and anaerobic bacteria isolated from diabetic foot infections, ceftobiprole MICs (μg/ml) at which 90% of the isolates tested were inhibited were as follows: methicillin-resistant Staphylococcus aureus, 1; methicillin-susceptible S. aureus and Staphylococcus lugdunensis, 0.5; Anaerococcus prevotii, 0.125; Finegoldia magna, 0.5; Peptoniphilus asaccharolyticus, 1; Peptostreptococcus anaerobius, 4; Escherichia coli and Enterobacter species, 0.125; Klebsiella species, 2; and Pseudomonas aeruginosa, 8.

Tigecycline was tested against 396 strains of lesser-known anaerobic species encountered in human infections. It was active against all gram-positive strains and 228 of 232 gram-negative anaerobes at ≤1 μg/ml. One strain of Prevotella oralis was nonsusceptible at 8 μg/ml.

Tests of dalbavancin's in vitro activity against 209 aerobic and 120 anaerobic isolates from pretreatment diabetic foot infections showed an MIC90 of ≤0.125 μg/ml against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and 120 anaerobes (Clostridium perfringens, other clostridia, Peptoniphilus asaccharolyticus, Finegoldia magna, and Anaerococcus prevotii), compared to respective MIC90s for MSSA and MRSA of 0.5 and 1 μg/ml for vancomycin, 4 and 4 μg/ml for linezolid, 0.5 and 0.5 μg/ml for daptomycin, and 0.25 and >8 μg/ml for clindamycin.

Daptomycin has in vitro activity against gram-positive anaerobic bacteria, although limited numbers of species have been tested. We studied the in vitro activities of daptomycin, vancomycin, and penicillin against more than 100 strains each of Clostridium difficile, C. perfringens, Finegoldia magna, and Propionibacterium acnes. Daptomycin Etest MICs and results from time-kill studies were determined for selected strains. For 392 of 421 strains (93%), daptomycin was inhibitory at ≤1 μg/ml, including 15 of 16 strains of C. difficile with elevated linezolid MICs of 8 and 16 μg/ml, all 32 strains with moxifloxacin MICs of ≥4 μg/ml, and all 16 strains resistant to clindamycin. Daptomycin MICs were also ≤1 μg/ml for all 16 F. magna strains resistant to clindamycin and all 32 strains resistant to tetracycline. Only one strain, a C. perfringens strain, had a MIC of >2 μg/ml to daptomycin. Eighty-five and 92.5% of the Etest MICs were within 1 dilution of the agar dilution method for all drugs at 24 and 48 h, respectively. In time-kill studies, a C. difficile strain was inhibited by both daptomycin and vancomycin at 1, 2, 4, 8, and 24 h; colony counts were decreased by 2.3 to 2.9 log at 24 h. Vancomycin was not bactericidal for C. perfringens; however, daptomycin showed bactericidal activity as early as 1 h at four and eight times the MIC and at 2 and 4 h at two and four times the MIC.

Using the NCCLS agar dilution method, we studied the in vitro activity of retapamulin (SB-275833) against 141 clinical isolates of Propionibacterium species, including seven multiresistant strains, and found retapamulin to be the most active agent among those tested with MICs of ≤1 μg/ml against all isolates.

The in vitro activity of moxifloxacin against 923 recent anaerobic isolates obtained from pretreatment cultures in patients with complicated intra-abdominal infections was studied using the CLSI M11-A-6 agar dilution method. Moxifloxacin was active against 87% (96 of 110) Bacteroides fragilis strains at ≤1 μg/ml and 87% (79 of 90) B. thetaiotaomicron strains at ≤2 μg/ml. Species variation was seen, with B. uniformis, B. vulgatus, Clostridium clostridioforme, and C. symbiosum being least susceptible and accounting for most of the resistant isolates; excluding the aforementioned four resistant species, 86% (303 of 363) of Bacteroides species isolates and 94% (417 of 450) of all other genera and species were susceptible to ≤2 μg/ml of moxifloxacin. Overall, moxifloxacin was active against 763 of 923 (83%) of strains at ≤2 μg/ml, supporting its use as a monotherapy for some community-acquired intra-abdominal infections.

Fourteen fluoroquinolone-resistant fusobacterial strains, originating from cats or dogs, were characterized by sequencing of the 16S-23S and 16S rRNA genes and DNA-DNA hybridization and were described as a new species, Fusobacterium canifelinum. All of the strains are intrinsically resistant (MIC, >4 g/ml) to levofloxacin and other fluoroquinolones. Compared to the quinolone resistance-determining region (gyrA) of the susceptible relative F. nucleatum, we found that Ser79 was replaced with leucine and Gly83 was replaced with arginine.