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Telithromycin (HMR 3647; RU 66647), a new ketolide, is a semisynthetic erythromycin A derivative characterized by a lack of L-cladinose and by having a 3-keto function. It has been demonstrated to be more active than macrolides against anaerobes (2, 6, 7) and erythromycin-A-resistant gram-positive cocci (efflux and inducible macrolides-lincosamides-streptogramin B) (3, 10, 12, 16).

Premarket in vitro testing focuses on the more typical bacterial pathogens, such as the Bacteroides fragilis group and Clostridium perfringens (2, 5, 6, 11). Previously, we reported telithromycin to be active against aerobic and anaerobic bite wound isolates (7). Since scant data exist on its activity against less-frequently isolated anaerobic pathogens, we determined telithromycin's comparative activity against a plethora of unusual, anaerobic, pathogenic species encountered in human clinical infections.

Strains were identified by standard criteria (1, 4, 8, 9, 13, 15). B. fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741 were tested simultaneously as control strains. The numbers and species of isolates tested and their susceptibilities are given in Table 1.

Standard laboratory powders were supplied as follows: telithromycin (HMR 3647), cefotaxime, and roxithromycin, Hoechst Marion Roussel, Romanville, France; trovafloxacin and azithromycin, Pfizer, Inc., New York, N.Y.; clarithromycin, Abbott Laboratories, Abbott Park, Ill.; clindamycin, Pharmacia Upjohn Co., Kalamazoo, Mich.; metronidazole, Searle Research & Development, Skokie, Ill.; amoxicillin-clavulanate, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.; erythromycin, Eli Lilly & Co., Indianapolis, Ind.; and penicillin G, Sigma Chemical Co., St. Louis, Mo.

Susceptibility testing was performed according to National Committee for Clinical Laboratory Standards standards (14). Brucella agar supplemented with hemin, vitamin K₁, and 5% laked sheep blood was the basal medium used. For Bilophila wadsworthia, the medium was also supplemented with pyruvate. Antimicrobial agents were reconstituted according to the manufacturers' instructions. Serial twofold dilutions of antimicrobial agents were prepared on the day of the test and were added to the medium in various concentrations. Agar plates were inoculated (10⁵ CFU per spot) with a Steers replicator (Craft Machine, Inc., Chester, Pa.).

Telithromycin MICs of <1 µg/ml were seen against many genera and species. There were marked interspecies and intraspecies differences in the susceptibilities of less-commonly identified anaerobes to telithromycin.

Actinomyces spp. had telithromycin MICs of 0.015 µg/ml and were generally susceptible to the other agents tested with the exception of trovafloxacin which had a MIC at which 90% of isolates were inhibited (MIC₉₀) of 4 µg/ml. Almost all (42 of 45) Peptostreptococcus species had telithromycin MIC₉₀s of 0.06 µg/ml (the exceptions were 2 of the 11 Peptostreptococcus asaccharolyticus isolates and 1 of the 9 Peptostreptococcus prevotii isolates). All 14 of the 45 Peptostreptococcus isolates that were resistant to one or more macrolides had telithromycin MICs of 1 µg/ml.

Telithromycin had MIC₉₀s of 1 µg/ml for Bacteroides species, including Bacteroides tectum, Bacteroides ureolyticus, and Campylobacter gracilis. Penicillin had a MIC of 4 µg/ml for 3 of 10 C. gracilis isolates. All Porphyromonas speciesPorphyromonas canoris, Porphyromonas gingivalis, and Porphyromonas macacaewere susceptible to <0.125 µg of telithromycin per ml except for 2 of 11 Porphyromonas asaccharolytica strains tested which were resistant (32 µg/ml) to telithromycin and consequently influenced the MIC₉₀ curve for that species.

Prevotella species were susceptible, with telithromycin MIC₉₀s as follows: Prevotella bivia, 0.5 µg/ml; Prevotella oris-buccae group, 1 µg/ml; Prevotella heparinolytica, 0.5 µg/ml; Prevotella intermedia, 0.06 µg/ml; and Prevotella melaninogenica, 2 µg/ml. Occasional strains from several genera were more resistant, which influenced the MIC ranges and occasionally the MIC₉₀s. For example, telithromycin had a MIC of 2 µg/ml for two strains of P. melaninogenica but had a MIC of 0.5 µg/ml for 10 P. melaninogenica strains; telithromycin had a MIC of >1 µg/ml for 3 of 22 P. oris-buccae group isolates, while 18 P. oris-buccae group isolates were susceptible to 0.5 µg of telithromycin per ml.

Telithromycin had a MIC₅₀ of 2 µg/ml and a MIC₉₀ of 4 µg/ml for both B. wadsworthia and Veillonella species. Telithromycin was more active on a weight basis than the other macrolides against Veillonella species and B. wadsworthia. Penicillin MICs for B. wadsworthia ranged from 2 to 16 µg/ml, and 4 of 16 isolates were resistant to trovafloxacin (MIC, >8 µg/ml). Anaerobiospirillum species were also in this intermediate group, with MICs ranging from 2 to 8 µg of telithromycin per ml; all isolates were resistant to clindamycin and also had metronidazole MICs of 1 to 8 µg/ml. Azithromycin was the most active macrolide against Anaerobiospirillum spp. (MICs ranging from 0.125 to 1 µg/ml).

The Clostridium species tested were generally susceptible to telithromycin at concentrations of 0.5 µg/ml, but in each species there seemed to be a biphasic pattern between very susceptible isolates and resistant strains. Clostridium clostridioforme tended to be more resistant, with penicillin MICs of >16 µg/ml for 2 of 11 isolates, and relative resistance to telithromycin was seen in 4 of 11 strains (MICs, >8 µg/ml), but all isolates were susceptible to clindamycin (MIC, <2 µg/ml). Clostridium innocuum had 7 of 13 strains with telithromycin MICs of >32 µg/ml and similar sensitivity to macrolides, including one strain that was also resistant to penicillin (MIC, >32 µg/ml). Seven of 10 Clostridium ramosum isolates were susceptible to telithromycin (MIC, 0.03 µg/ml) and other macrolides; none were resistant to clindamycin.

The fusobacteria were problematic for telithromycin and the macrolides. Fusobacterium ulcerans and Fusobacterium varium tend to be resistant to the agents (MIC₉₀, >16 µg/ml), while 9 of 12 Fusobacterium russii isolates tended to be susceptible (MIC, 1 µg/ml). The other Fusobacterium species did not show any distinct trends.

Several differences exist between our study and those of others, including the variety of isolates studied, the agar media used, and the inoculum employed. Jones and Biedenbach (11) reported that the MIC of telithromycin for B. fragilis group species (no data shown and agar used not elucidated) was >8 µg/ml. Boswell et al. (2) used an inoculum of 10⁴ CFU/ml and Wilkins Chalgren media supplemented with 50 mg of 1-(4-nitrophenyl)-glycerol per liter in order to study 53 strains of B. fragilis (telithromycin MIC₉₀, 2 µg/ml), 10 strains of C. perfringens and Clostridium difficile (telithromycin MIC₉₀s, 0.06 and 1 µg/ml, respectively), and 20 strains of Peptostreptococcus species (telithromycin MIC₉₀, 0.008 µg/ml). Ednie et al. (6) studied a larger variety of anaerobes using Oxyrase supplementation and did identify many isolates to species level; most of their isolates were of species different than those tested in our study. When the same species were tested, the resulting MIC₉₀ results were similar for P. bivia, P. intermedia, and peptostreptococci in both studies. In all studies so far, the peptostreptococci have been uniformly susceptible to telithromycin (MIC₉₀s, 0.06 µg/ml) (2, 5, 6, 7). Our isolates of P. melaninogenica were slightly more resistant to telithromycin than those reported by Ednie et al. (6) (MIC₉₀ of 2 µg/ml versus 0.25 µg/ml, respectively).

Since clinicians must rely on published studies to help guide both empirical therapy and specific therapy in situations that involve commonly and less-commonly isolated or identified anaerobes in mixed infections (2, 5, 11), our study suggests that telithromycin (HMR 3647) has in vitro activity against unusual anaerobes and merits further evaluation.