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The novel fluorocycline antibiotic eravacycline is in development for use in the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDR Bacteroides spp. and Clostridium difficile Eravacycline was potent in vitro against all the isolates tested, including strains with tetracycline-specific resistance determinants and MDR anaerobic pathogens resistant to carbapenems and/or β-lactam-β-lactamase inhibitor combinations., (Copyright © 2018 American Society for Microbiology.)

We evaluated the in vitro activity of imipenem-relebactam (imipenem-MK7655) against 451 recent clinical isolates within the Bacteroides group and related species. Relebactam did not enhance or inhibit the activity of imipenem against Bacteroides fragilis or other Bacteroides species. No synergistic or antagonistic effect was observed. The MICs of imipenem-relebactam were equal to or within one dilution of the MICs of these isolates to imipenem., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

In 2011 a surveillance study for the susceptibility to fidaxomicin and epidemiology of Clostridium difficile isolates in the United States was undertaken in seven geographically dispersed medical centers. This report encompasses baseline surveillance in 2011 and 2012 on 925 isolates. A convenience sample of C. difficile isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution (CLSI M11-A8). Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration, or European Union of Clinical Antimicrobial Susceptibility Testing (EUCAST) breakpoints were applied where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of 322 strains, stratified by institution, underwent restriction endonuclease analysis (REA). The fidaxomicin MIC90 was 0.5 μg/ml for all isolates regardless of REA type or toxin gene profile, and all isolates were inhibited at ≤1.0 μg/ml. By REA typing, BI strains represented 25.5% of the isolates. The toxin gene profile of tcdA, tcdB, and cdtA/B positive with a tcdC 18-bp deletion correlated with BI REA group. Moxifloxacin and clindamycin resistance was increased among either BI or binary toxin-positive isolates. Metronidazole and vancomycin showed reduced susceptibility (EUCAST criteria) in these isolates. Geographic variations in susceptibility, REA group and binary toxin gene presence were observed. Fidaxomicin activity against C. difficile isolated in a national surveillance study did not change more than 1 year after licensure. This analysis provides baseline results for future comparisons., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

We evaluated in vitro activity of ceftolozane-tazobactam (TOL-TAZ), formerly CXA-201, against recent clinical anaerobic isolates with emphasis on the Bacteroides fragilis group. Ceftolozane-tazobactam showed good activity against B. fragilis species and intermediate to limited activity against other species of Bacteroides. Ceftolozane-tazobactam showed very good activity against Prevotella spp., Fusobacterium spp., and Propionibacterium spp., varying activities against Gram-positive cocci, and limited activity against Clostridium spp.

We evaluated the activity of CB-183,315 against Clostridium difficile, including strains that are resistant to fluoroquinolones and metronidazole and with elevated MICs to vancomycin as well as other Gram-positive intestinal pathogens. The MICs of CB-183,315 against all C. difficile isolates were ≤ 1 μg/ml. CB-183,315 had greater activity than vancomycin and metronidazole against C. difficile isolates and was more active than the comparators against vancomycin-resistant enterococcus (VRE). CB-183,315 also had excellent activity against methicillin-resistant Staphylococcus aureus (MRSA), other Clostridium spp., and Peptostreptococcus spp.

The in vitro activity of ceftaroline was compared with those of ceftriaxone, clindamycin, imipenem, metronidazole, moxifloxacin, tigecycline, and vancomycin against 514 clinical anaerobic isolates using Clinical and Laboratory Standards Institute (CLSI) standard methodology. Ceftaroline demonstrated good to excellent activity against Gram-positive anaerobic pathogens and limited activity against Gram-negative pathogens, particularly Bacteroides fragilis group isolates.

Background: The rationale and lessons learned through the evolution of the National Survey for the Susceptibility of Bacteroides fragilis Group from its initiation in 1981 through 2007 are reviewed here. The survey was conceived in 1980 to track emerging antimicrobial resistance in Bacteroides species., Methods: Data from the last 11 years of the survey (1997-2007), including 6574 isolates from 13 medical centers, were analyzed for in vitro antimicrobial resistance to both frequently used and newly developed anti-anaerobic agents. The minimum inhibitory concentrations of the antibiotics were determined using agar dilution in accordance with Clinical and Laboratory Standards Institute recommendations., Results: The analyses revealed that the carbapenems (imipenem, meropenem, ertapenem, and doripenem) and piperacillin-tazobactam were the most active agents against these pathogens, with resistance rates of 0.9%-2.3%. In the most recent 3 years of the survey (2005-2007), resistance to some agents was shown to depend on the species, such as ampicillin-sulbactam against Bacteroides distasonis (20.6%) and tigecycline against Bacteroides uniformis and Bacteroides eggerthii ( approximately 7%). Very high resistance rates (>50%) were noted for moxifloxacin and trovafloxacin, particularly against Bacteroides vulgatus. During that period of study, non-B. fragilis Bacteroides species had >40% resistance to clindamycin. Metronidazole-resistant Bacteroides strains were also first reported during that period., Conclusions: In summary, resistance to antibiotics was greater among non-B. fragilis Bacteroides species than among B. fragilis and was especially greater among species with a low frequency of isolation, such as Bacteroides caccae and B. uniformis. The emergence of resistance among the non-B. fragilis Bacteroides species underscores the need for speciation of B. fragilis group isolates and for clinicians to be aware of associations between species and drug resistance.

Doripenem was evaluated against 527 recent clinical isolates, i.e., 404 Bacteroides fragilis isolates and 123 gram-positive anaerobe isolates. Against B. fragilis, doripenem was as active as imipenem, meropenem, and piperacillin-tazobactam and more active than ertapenem or ampicillin-sulbactam. Doripenem was active against isolates resistant to ertapenem, ampicillin-sulbactam, cefoxitin, clindamycin, and moxifloxacin. All of the gram-positive isolates tested were susceptible to doripenem.

The susceptibility trends for the species of the Bacteroides fragilis group against various antibiotics from 1997 to 2004 were determined by using data for 5,225 isolates referred by 10 medical centers. The antibiotic test panel included ertapenem, imipenem, meropenem, ampicillin-sulbactam, piperacillin-tazobactam, cefoxitin, clindamycin, moxifloxacin, tigecycline, chloramphenicol, and metronidazole. From 1997 to 2004 there were decreases in the geometric mean (GM) MICs of imipenem, meropenem, piperacillin-tazobactam, and cefoxitin for many of the species within the group. B. distasonis showed the highest rates of resistance to most of the beta-lactams. B. fragilis, B. ovatus, and B. thetaiotaomicron showed significantly higher GM MICs and rates of resistance to clindamycin over time. The rate of resistance to moxifloxacin of B. vulgatus was very high (MIC range for the 8-year study period, 38% to 66%). B. fragilis, B. ovatus, and B. distasonis and other Bacteroides spp. exhibited significant increases in the rates of resistance to moxifloxacin over the 8 years. Resistance rates and GM MICs for tigecycline were low and stable during the 5-year period over which this agent was studied. All isolates were susceptible to chloramphenicol (MICs < 16 microg/ml). In 2002, one isolate resistant to metronidazole (MIC = 64 microg/ml) was noted. These data indicate changes in susceptibility over time; surprisingly, some antimicrobial agents are more active now than they were 5 years ago.

The in vitro activities of tigecycline were tested against 831 isolates of the Bacteroides fragilis group representing all of the species within the group. On a weight-to-weight basis (8 microg/ml), tigecycline was more active than clindamycin, minocycline, trovafloxacin, and cefoxitin and less active than imipenem or piperacillin-tazobactam against all isolates of the B. fragilis group. Tigecycline geometric mean MICs were statistically higher against B. distasonis than other Bacteroides species (P value of 0.0001).

The activities of BMS-284576, clinafloxacin, moxifloxacin, sitafloxacin, trovafloxacin, imipenem, cefoxitin, and clindamycin against 589 Bacteroides fragilis group isolates were determined. The activity of BMS-284576 was comparable to that of trovafloxacin. Sitafloxacin and clinafloxacin were the most active quinolones, and moxifloxacin was the least active. B. fragilis was the most susceptible of the species, and Bacteroides vulgatus was the most resistant. Association of specific antibiotic resistance with Bacteroides species was noted for all quinolones.

The results of a multicenter US survey using the National Committee for Clinical Laboratory Standards currently recommended methodology for measuring in vitro susceptibility of 2673 isolates of Bacteroides fragilis group species were compared from 1997 to 2000. The test panel consisted of 14 antibiotics: 3 carbapenems, 3 beta-lactam-beta-lactamase inhibitors, 3 cephamycins, 2 fluoroquinolones, clindamycin, chloramphenicol, and metronidazole. Declines in the geometric mean minimum inhibitory concentrations were seen with imipenem, meropenem, ampicillin-sulbactam, and the cephamycins. Increased geometric means were observed with the fluoroquinolones and were usually accompanied by an increase in resistance rates. Bacteroides distasonis shows the highest resistance rates among beta-lactam antibiotics, whereas Bacteroides vulgatus shows the highest resistance levels among fluoroquinolones. B. fragilis shows the lowest resistance rates for all antibiotics. All strains were susceptible to chloramphenicol and metronidazole concentrations <8 microgram/mL. The data underscore the need for species identification and continued surveillance to monitor resistance patterns.

The in vitro activity of daptomycin against 224 current gram-positive clinical isolates including vancomycin-resistant Enterococcus faecium (VREF), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus spp. (MRSS), and penicillin-resistant Streptococcus pneumoniae (PRSP) was evaluated. The MICs at which 90% of isolates are inhibited for daptomycin and vancomycin, respectively, were as follows: MRSA, 1 and 2 microg/ml; MRSS, 1 and 4 microg/ml; PRSP, 1 and 0.5 microg/ml; and VREF, 2 and >64 microg/ml. Daptomycin was bactericidal against 82% of 17 VREF isolates. The antibacterial activity of daptomycin was strongly dependent on the calcium concentration of the medium. Daptomycin was active against all gram-positive cocci tested.

The in vitro antibacterial activities of clinafloxacin, trovafloxacin, ciprofloxacin, and cefoxitin against 1,000 clinical isolates of Bacteroides fragilis group were compared by agar dilution in brucella blood agar (BBA) and Wilkins Chalgren agar (WCA). Significantly higher geometric mean MICs for the three quinolones and cefoxitin (P<0.001) were obtained in BBA than in WCA. Regardless of medium, clinafloxacin was slightly more active than trovafloxacin. The activity of clinafloxacin and trovafloxacin was greater than that of cefoxitin against B. distasonis, B. ovatus, and B. thetaiotaomicron but lower against B. vulgatus. High cross resistance between trovafloxacin and clinafloxacin was observed.

Antimicrobial resistance, including plasmid-mediated resistance, among the species of the Bacteroides fragilis group is well documented. An analysis of the in vitro susceptibility of B. fragilis group species referred between 1995 and 1996 as well as during a 7-year (1990 to 1996), prospective, multicenter survey of over 4,000 clinical isolates of B. fragilis group species was undertaken to review trends in the percent resistance to and geometric mean MICs of the antibiotics tested. There was a trend toward a decrease in the geometric mean MICs of most beta-lactam antibiotics, while the percent resistance to most agents was less affected. Within the species B. fragilis, the geometric mean MICs showed significant (P < 0.05) decreases for piperacillin-tazobactam, ticarcillin-clavulanate, piperacillin, ticarcillin, ceftizoxime, cefotetan, and cefmetazole; a significant increase was observed for clindamycin and cefoxitin. For the non-B. fragilis species, a significant decrease in the geometric mean MICs was observed for meropenem, ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin, ticarcillin, ceftizoxime, and cefmetazole; a significant increase was observed for cefoxitin. Significant increases in percent resistance were observed within the B. fragilis strains for ticarcillin and ceftizoxime and within the non-B. fragilis isolates for cefotetan. Significant increases in percent resistance among all B. fragilis group species were observed for clindamycin, while imipenem showed no significant change in resistance trends. The trend analysis for trovafloxacin was limited to 3 years, since the quinolone was tested only in 1994, 1995, and 1996. During the 7 years analyzed, there was no resistance to metronidazole or chloramphenicol observed. The data demonstrate that resistance among the B. fragilis group species has decreased in the past several years, the major exception being clindamycin. The majority of the resistance decrease has been for the beta-lactams in B. fragilis, compared to other species. The reasons for these changes are not readily apparent.

The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 microgram/ml, showed good activity against strains expressing tet(M) (ribosomal protection), tet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, < or = 0.5 microgram/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet(K) or tet(M) resistance determinants (median effective doses [ED50s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.

A series of novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs with L-amino acids demonstrated improved efficacy after oral administration, while the D forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of < 1 mg/kg against infections caused by S. aureus, E. coli, Enterobacter cloacae, or penicillin-susceptible Streptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii, Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to > 32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.

CL 188,624, CL 190,294, and CL 191,121 are novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems. The in vitro antibacterial activities of these THF carbapenems were evaluated and compared with those of biapenem, imipenem, and meropenem against 554 recent clinical isolates obtained from geographically distinct medical centers across North America. The antibacterial activities of the THF carbapenems were equivalent to that of biapenem, and the THF carbapenems were slightly more active than imipenem and less active than meropenem against most of the members of the family Enterobacteriaceae but lacked significant activity against Pseudomonas isolates. In general, CL 191,121 was two- to fourfold more active than CL 188,624 and CL 190,294 against the staphylococcal and enterococcal isolates tested. CL 191,121 was twofold less active than imipenem against methicillin-susceptible staphylococci and was as activity as imipenem against Enterococcus faecalis isolates. Biapenem and meropenem were two- and fourfold less active than CL 191,121, respectively, against the methicillin-susceptible staphylococci and E. faecalis. All the carbapenems displayed equivalent good activities against the streptococci. Biapenem was slightly more active than the other carbapenems against Bacteroides fragilis isolates. Time-kill curve studies demonstrated that the THF carbapenems were bactericidal in 6 h against Escherichia coli and Staphylococcus aureus isolates. The postantibiotic effect exerted by CL 191,121 was comparable to or slightly longer than that of imipenem against isolates of S. aureus, E. coli, and Klebsiella pneumoniae.

TEM-28 (pI 6.1), expressed by an Escherichia coli clinical isolate, is a novel beta-lactamase which hydrolyzed ceftazidime, cefotaxime, and aztreonam with rates of 25, 1.1, and 5.6, respectively, relative to that for benzylpenicillin (100). The nucleotide sequence of blaTEM-28 differed from that of blaTEM-1 by two base changes, resulting in amino acid substitutions of Arg-164 to His and Glu-240 to Lys.

The bioxalomycins, a novel complex of broad-spectrum antibiotics, were isolated from fermentations of Streptomyces viridodiastaticus subsp. "litoralis" LL-31F508. Bioxalomycin alpha 2, the major component of this complex, exhibited antibacterial activity. The MICs ranged from < or = 0.002 to 0.008 micrograms/ml for gram-positive organisms and from 0.50 to 4 micrograms/ml for gram-negative organisms. Bioxalomycin alpha 2 was found to be bactericidal and to inhibit bacterial DNA synthesis preferentially. Bioxalomycin alpha 2 protected mice from a lethal challenge with Staphylococcus aureus Smith. The 50% effective dose of bioxalomycin alpha 2 administered orally was 10 times greater than that when the drug was given subcutaneously or intravenously. These data suggest a stability or bioavailability problem when the compound is administered orally.

N,N-Dimethylglycylamido (DMG) derivatives of minocycline and 6-demethyl-6-deoxytetracycline are new semisynthetic tetracyclines referred to as the glycylcyclines. The in vitro activities of the glycylcyclines were evaluated in comparison with those of minocycline and tetracycline against strains carrying characterized tetracycline resistance determinants and against 995 recent clinical isolates obtained from geographically distinct medical centers in North America. The glycylcyclines were active against tetracycline-resistant strains carrying efflux [tet(A), tet(B), tet(C), and tet(D) in Escherichia coli and tet(K) in Staphylococcus aureus] and ribosomal protection [tet(M) in S. aureus, Enterococcus faecalis, and E. coli)] resistance determinants. Potent activity (MIC for 90% of strains, < or = 0.5 microgram/ml) was obtained with the glycylcyclines against methicillin-susceptible and methicillin-resistant S. aureus, E. faecalis, Enterococcus faecium, and various streptococcal species. The glycylcyclines exhibited good activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to minocycline and tetracycline. The activities of the glycylcyclines against most organisms tested were comparable to each other. The in vivo efficacies of the glycylcyclines against acute lethal infections in mice when dosed intravenously were reflective of their in vitro activities. The glycylcyclines had efficacies comparable to that of minocycline against infections with methicillin-susceptible and methicillin-resistant S. aureus strains, a strain carrying tet(K), and a tetracycline-susceptible E. coli strain but exceeded the effectiveness of minocycline against infections with resistant isolates, including strains harboring tet(M) or tet(B). Levels of DMG-6-deoxytetracycline in serum were higher and more sustained than those of DMG-minocycline or minocycline. Our results show that the glycylcyclines have potent in vitro activities against a wide spectrum of gram-positive and gram-negative, aerobic and anaerobic bacteria, including many resistant strains. On the basis of their in vitro and in vivo activities, the glycylcyclines represent a significant advance to the tetracycline class of antibiotics and have good potential value for clinical efficacy.

The activity of LJC10,627 was compared with the activities of imipenem and other antibiotics. LJC10,627 was more active against most members of the family Enterobacteriaceae, Pseudomonas spp., and Acinetobacter spp. but slightly less active than imipenem against staphylococci and streptococci. LJC10,627 showed stability to mouse dehydropeptidase I and was more effective in vivo than imipenem plus cilastatin against gram-negative bacterial infections and as effective against staphylococcal infections.

A nationwide susceptibility survey of 557 isolates of the Bacteroides fragilis group was continued in 1986. The most active beta-lactam drugs were imipenem and ticarcillin-clavulanic acid, which had 0.2 and 1.7% resistance, respectively. The rank order of activity of beta-lactam drugs was imipenem, ticarcillin-clavulanic acid, cefoxitin, piperacillin, moxalactam, ceftizoxime, cefotetan, cefotaxime, cefoperazone, and ceftazadime.

The activity of cefbuperazone was tested in vitro against 287 clinical isolates of Bacteroides spp. Cefbuperazone showed good activity against B. fragilis, B. vulgatus, and other Bacteroides species, comparable to that of cefoxitin. It was relatively ineffective against B. distasonis and the B. thetaiotaomicron-ovatus group and was not active against cefoxitin-resistant Bacteroides spp.

A nationwide susceptibility survey of the Bacteroides fragilis group was continued at New England Medical Center in 1983. A total of 555 strains were obtained from eight centers in the United States. In addition to the nine antimicrobial agents studied in the two previous years, three other agents were added to the evaluation: cefamandole, cefuroxime, and cefonicid. The results for the strains tested with the original nine drugs in 1983 were compared with those for 1,292 isolates tested in 1981 and 1982. The most active beta-lactam drug was piperacillin, which had an 8% resistance rate. Cefoxitin resistance increased from 10% in 1982 to 16% in 1983. High rates of resistance to cefotaxime, cefoperazone, cefamandole, cefonicid, and cefuroxime were encountered. No metronidazole- or chloramphenicol-resistant isolates were found during the 3 years of the study. Susceptibility patterns varied at the eight hospitals: the outbreak of cefoxitin resistance reported in 1982 at New England Medical Center remitted, while a high clindamycin resistance rate was documented at one hospital in 1983. These data indicate the need for determining the susceptibility patterns for the B. fragilis group of organisms at each hospital.

The in vitro activity of trospectomycin (U-63366; 6'-n-propyl spectinomycin pentahydrate sulfate) was evaluated against 189 clinical isolates of the Bacteroides fragilis group and 65 Bacteroides species isolates. At less than or equal to 8 micrograms/ml, the activity of trospectomycin compared favorably with those of clindamycin and cefoxitin against B. fragilis, Bacteroides distasonis, and Bacteroides vulgatus, and there was no cross resistance to these three drugs among the strains of the B. fragilis group. All the Bacteroides species were susceptible to trospectomycin. The results of this in vitro study indicate that trospectomycin possesses excellent activity against Bacteroides species.

We compared the effects of four beta-lactam drugs with widely differing antibacterial and pharmacological properties on the composition of the intestinal flora. Cefoxitin, piperacillin, cefoperazone, and aztreonam were given intravenously for 9 days to healthy volunteers. Cefoperazone reduced the numbers of aerobic and anaerobic bacteria to undetectable levels. At the other extreme, cefoxitin had little effect on the normal flora. Aztreonam markedly reduced the numbers of aerobes, whereas piperacillin had a variable effect on both aerobic and anaerobic bacteria. There was extensive overgrowth of enterococci in subjects given cefoxitin or aztreonam, which have little activity against this species, and of yeasts in subjects given cefoperazone or piperacillin. Cefoperazone reached concentrations of 2,727 to 8,840 micrograms/g in the feces, whereas the other agents were generally undetectable. These results show that the new beta-lactam antibiotics produce widely varying effects on the fecal microflora after parenteral administration and that these effects are consistent with the antibacterial and pharmacological properties of the drugs.

Clindamycin resistance in Bacteroides fragilis was examined in 507 strains isolated from 1973 to 1981. Three groups were recognized: highly susceptible (minimum inhibitory concentration [MIC] less than or equal to 0.125 microgram/ml), intermediately susceptible (MIC = 0.25 to 4 micrograms/ml), and highly resistant to (MIC greater than or equal to 8 microgram/ml). The incidence of high-level resistance (1.8%) had not changed during this period. Only 8 of 17 isolates reputed to be highly clindamycin resistant that were referred to our laboratory proved to be highly resistant (MICs greater than or equal to 32 microgram/ml), whereas the other 9 were intermediately susceptible. Analysis of 2- and 10-microgram clindamycin disks for determining the susceptibility of B. fragilis revealed a high false-resistance rate with the 2-microgram disk, most errors occurring with the intermediate group. There was no false resistance with the 10-microgram disk. When disk diffusion susceptibility of B. fragilis is employed, we recommend the 10-microgram disk to predict accurately the susceptibility of B. fragilis to clindamycin.

Twenty-two anaerobic bacteria isolated from infected sites and normal fecal flora were assayed for superoxide dismutase (SOD). The organisms were also classified according to their oxygen tolerance into aerotolerant, intermediate, and extremely oxygen-sensitive groups. There was a correlation between the enzyme level and the oxygen tolerance, in that the aerotolerant and intermediate organisms had SOD, whereas the extremely oxygen-sensitive isolates had low or undetectable enzyme. Among the oxygen-tolerant organisms, gram-negative bacteria had higher levels of SOD than gram-positive organisms. Oxygen was shown to induce SOD production in a strain of Bacteriodes fragilis grown in minimal medium under continuous-culture conditions. Enzyme levels in this isolate grown under static conditions were lower in minimal medium than in complex medium, indicating that other components in the complex medium were stimulating the production of SOD. Our data suggest that the variation in oxygen tolerance of anaerobes is usually related to their level of SOD. It is postulated that SOD may be a virulence factor that allows pathogenic anaerobes to survive in oxygenated tissues until the proper reduced conditions are established for their growth.

The in vitro activity of thienamycin was tested against 135 aerobic and anaerobic bacteria. The compound was highly active against resistant gram-negative bacilli and penicillin-resistant Straphylococcus aureus. The antianaerobic spectrum of the drug seemed to be comparable to that of metronidazole.

We have surveyed the susceptibility of 1,575 clinical isolates of the Bacteroides fragilis group of organisms to cefoxitin and eight other antimicrobial agents. Eleven isolates, 0.7% of the total, were highly cefoxitin resistant and had minimum inhibitory concentrations of greater than or equal to 64 micrograms/ml. These isolates were also resistant to other beta-lactam antibiotics. Of 11 isolates, 4 were able to inactivate cefoxitin in broth cultures, as measured by microbiological and high-pressure liquid chromatography assays. Two distinct patterns of cefoxitin breakdown products were detected by high-pressure liquid chromatography analysis. The beta-lactamase inhibitors clavulanic acid and sulbactam failed to show synergism with cefoxitin. These data demonstrate that members of the B. fragilis group have acquired a novel resistance mechanism enabling them to inactivate cefoxitin.

The in vitro activity of N-formimidoyl thienamycin (MK0787), a stable congener of thienamycin, was determined against 200 species of aerobic and 84 species of anaerobic bacteria. The compound was highly active against resistant gram-negative bacilli, penicillin-resistant Staphylococcus aureus, enterococci, and anaerobic bacteria. The new derivative of thienamycin was more active than the parent compound, probably reflecting the stability of the analog.

The in vitro susceptibility of 162 anaerobic isolates from clinical material were tested to pencillin G, BL-P1654, and carbenicillin. Penicillin G and BL-P1654 showed good activity against Bacteroides fragilis, but only 60% of strains were susceptible to carbenicillin at achievable blood levels (128 mug/ml).

The in vitro susceptibility of 155 strains of anaerobic bacteria to five cephalosporin antibiotics was tested. Cefoxitin was the most active against 33 isolates of Bacteroides fragilis; 82% of the strains were sensitive at 16 mug/ml. At 64 mug/ml cefazolin and cephaloridine were also generally effective. Cephalothin and cephalexin were relatively inactive versus B. fragilis. Cefoxitin, cephaloridine, cefazolin, and cephalothin showed comparable activity against 122 strains of anaerobes other than B. fragilis. More than 90% of the strains were sensitive to each of these antimicrobials at 16 mug/ml. Cephalexin was the least effective cephalosporin against all species tested.

The minimal inhibitory concentrations of nine antimicrobial agents was determined for over 750 clinical isolates of the Bacteroides fragilis group of anaerobic bacteria collected from nine centers in the United States during 1981. High resistance rates were documented for cefoperazone, cefotaxime, and tetracycline. Cefoxitin had the best activity of the beta-lactam antibiotics, whereas moxalactam and piperacillin had good activities. The resistance rate for clindamycin was 6%. There were no metronidazole- or chloramphenicol-resistant isolates encountered. There were significant differences in susceptibility among the various species of the B. fragilis group, particularly with moxalactam, cefoxitin, and clindamycin. Clustering of clindamycin-, piperacillin-, and cefoxitin-resistant isolates was observed at different hospitals. The variability of resistance rates with the beta-lactam antibiotics and clindamycin indicates that susceptibility testing of significant clinical isolates should be performed to define local resistance patterns.

Lactobacillus sp. strain GG, which was isolated from the feces of a normal person, produced a substance with potent inhibitory activity against a wide range of bacterial species. It inhibited anaerobic bacteria (Clostridium spp., Bacteroides spp., Bifidobacterium spp.), members of the family Enterobacteriaceae, Pseudomonas spp. Staphylococcus spp., and Streptococcus spp., as demonstrated by a microbiological assay; however, it did not inhibit other lactobacilli. The inhibitory activity occurred between pH 3 and 5 and was heat stable. Bactericidal activity against Escherichia coli was demonstrated at a dilution of 1:128. The inhibitory substance was distinct from lactic and acetic acids. It had a low molecular weight (less than 1,000) and was soluble in acetone-water (10:1). Because of these characteristics, the inhibitory material could not be considered a bacteriocin; it most closely resembled a microcin, which has been associated previously with members of the family Enterobacteriaceae.

Tazobactam (YTR-830H), a novel beta-lactamase inhibitor, was compared with clavulanic acid and sulbactam for enhancement of the activity of piperacillin against beta-lactamase-producing, piperacillin-resistant clinical isolates. Piperacillin MICs were determined in media containing a fixed concentration of 2 or 4 micrograms of the inhibitors per ml. The higher concentration was generally more effective. Tazobactam was superior to sulbactam in enhancing the spectrum and potency of piperacillin. Although the calvulanic acid combination was more potent, tazobactam was effective for a similar spectrum of resistant gram-negative clinical isolates containing beta-lactamase. MICs were reduced to the susceptible range for Escherichia coli, Klebsiella pneumoniae, Proteus spp., Salmonella spp., and Shigella spp. Combinations with tazobactam and sulbactam, but not clavulanic acid, were effective against Morganella spp. Some antagonism of the activity of piperacillin was observed with clavulanic acid but not with tazobactam or sulbactam. The inhibitors were similarly effective with piperacillin against beta-lactamase-positive Staphylococcus spp. and the Bacteroides fragilis group. Piperacillin-tazobactam was more effective against a broader spectrum of gram-negative enteric bacteria than ticarcillin plus clavulanic acid was. Combinations with tazobactam or clavulanic acid had a broader spectrum of activity than combinations with sulbactam against bacteria that produce characterized plasmid-mediated enzymes of clinical significance. In particular, piperacillin with tazobactam or clavulanic acid, but not with sulbactam, inhibited TEM-1, TEM-2, and SHV-1 enzymes. In vitro activity was reflected in vivo. Tazobactam and clavulanic acid were superior to sulbactam in enhancing the therapeutic efficacy of piperacillin in mice infected with beta-lactamase-positive E. coli, K. pneumoniae, Proteus mirabilis, and Staphylococcus aureus. Only combinations with tazobactam and sulbactam were effective against the Morganella infection. Tazobactam has a good potential for enhancing the clinical efficacy of piperacillin.

An ongoing survey of the susceptibility of the Bacteroides fragilis group of bacteria was continued at New England Medical Center in 1984 and 1985. A total of 1,229 strains were obtained from eight centers in the United States. These results were compared with those for 1,847 isolates tested in 1981 through 1983. The most active beta-lactam drugs were imipenem and ticarcillin-clavulanic acid (Timentin), which had a less than 1% resistance rate. No metronidazole- or chloramphenicol-resistant isolates were found during the 5 years of the study. Isolates obtained from blood, perinatal, and bone sites of infection were more resistant to a variety of antimicrobial agents. Susceptibility patterns of the members of the B. fragilis group varied at the eight hospitals and among species. These data indicate the need for determining the susceptibility patterns for the B. fragilis group of organisms at each hospital.

Win 49375 had excellent activity against members of the family Enterobacteriaceae and staphylococcal species. Its activity against Pseudomonas aeruginosa was equal to that of gentamicin. Win 49375 had moderate activity against clostridia but little against Bacteroides fragilis. The drug showed a marked inoculum effect at 10(8) CFU/ml and a slight decrease in potency at pH 5.

Two members of the Bacteroides fragilis group, B. ovatus and B. thetaiotaomicron, are difficult to distinguish by biochemical methods. They are currently identified on the basis of their variable ability to ferment salicin. We studied a method of identification for these two species by using cell lysis by bacteriophages. A total of 38 bacteriophages were used to distinguish the two species. Identification by bacteriophages was compared with species identification by prereduced anaerobically sterilized biochemical testing with salicin as the differentiating test. A total of 215 clinical isolates biochemically identified as B. ovatus or B. thetaiotaomicron were tested. A total of 100% of the strains identified as B. ovatus by bacteriophages produced strong acid in salicin (pH less than or equal to 5.4). However, 40% of the strains identified as B. thetaiotaomicron by bacteriophages also produced strong acid in salicin, and an additional 39% produced weak acid (pH 5.5 to 5.7). This study demonstrates that salicin fermentation is an inadequate test for the differentiation of B. ovatus and B. thetaiotaomicron.

The activity of LY127935, a beta-lactam antibiotic of novel structure, was studied in vitro against facultative gram-negative bacilli, Staphylococcus aureus, and Bacteroides fragilis. The strains were recent clinical isolates, many of which were relatively resistant to other antibiotics. LY127935 exhibited striking activity against Escherichia coli, Klebsiella pneumoniae, Enterobacter sp., Proteus sp., Serratia marcescens, and B. fragilis with median minimum inhibitory concentrations of less than or equal to 1.0 micrograms/ml. It was somewhat less active against Pseudomonas aeruginosa and S. aureus. Cefotaxime (HR 756) showed very similar activity except that it was substantially weaker against B. fragilis. LY127935 was more active than cefamandole, cefoxitin, or piperacillin; it was also as potent as tobramycin or amikacin against all species except for P. aeruginosa.

The activity of cefamandole was comparable to that of cephalothin, cefazolin, and cephaloridine against Staphylococcus aureus, Streptococcus pyogenes, and Diplococcus pneumoniae. In contrast, cefamandole was considerably more active than cephalothin, cefazolin, or cephaloridine against gram-negative facultative bacilli, including Haemophilus influenzae, the most striking disparities being noted with indole-positive Proteus and Enterobacter. Bacteroides fragilis was more susceptible to cefoxitin than to cefamandole or cefazolin (median minimal inhibitory concentration, approximately 8, 32, and 32 mug/ml, respectively); cephalothin exhibited still less activity against this species. The majority of other anaerobes were inhibited by relatively low concentrations of all four cephalosporins. The results indicate a potentially valuable role for cefamandole against facultative gram-negative bacilli, including H. influenzae, but no exceptional activity against anaerobes.

We studied the activity of azthreonam (SQ 26,776), a novel monocyclic beta-lactam compound, against a variety of clinical isolates. It was more potent than moxalactam, cefoperazone, cefamandole, cefoxitin, ticarcillin, tobramycin, or amikacin against strains of Klebsiella spp., Serratia spp., and the Proteus group. It was highly effective against Escherichia coli and strains of Salmonella spp. The median minimal inhibitory concentration for all species of Enterobacteriaceae was less than or equal to 2 micrograms/ml. Azthreonam was moderately active against Pseudomonas aeruginosa, including tobramycin-resistant strains, and against Pseudomonas cepacia (median minimal inhibitory concentration, 16 to 32 micrograms/ml), but was weakly active against Pseudomonas maltophilia and strains of Acinetobacter spp. and Achromobacter spp. The drug showed little activity against Staphylococcus aureus, enterococci, and anaerobic bacteria, including Bacteroides fragilis, Clostridium spp., and gram-positive cocci. Like moxalactam and cefoperazone, azthreonam exhibited a considerable inoculum effect with strains of Enterobacter spp. and Pseudomonas spp. Combination with clavulanic acid did not increase the activity of azthreonam against S. aureus but was synergistic for 5 of 15 strains of B. fragilis. Azthreonam is about 50% bound to human serum protein. The selective range of activity of this compound could be of clinical benefit.

Studies with animals have shown that the normal intestinal microflora protects against colonization by new strains ("colonization resistance") and that this protective effect may be related to the anaerobic component of the microflora. However, colonization resistance has not been shown in humans. We administered cefoxitin, piperacillin, cefoperazone, and aztreonam intravenously to healthy subjects for 9 days and monitored the acquisition of new isolates in the fecal flora. Seven of sixteen antibiotic-treated subjects but none of four untreated controls became colonized by gram-negative bacilli. However, there was no correlation between colonization and the particular drug given or the extent of suppression of anaerobes or of any other component of the fecal microflora. Cefoxitin and piperacillin were associated with the greatest increases in the numbers of drug-resistant bacteria and in fecal beta-lactamase content. The results of this study support the concept that colonization resistance occurs in humans and is diminished by antibiotic administration but fail to support the hypothesis that resistance is related to the anaerobic microflora.

A susceptibility survey of 537 strains of the Bacteroides fragilis group from eight centers in the United States was continued at the Tufts New England Medical Center in 1982. The results were compared with those of 755 organisms analyzed in 1981. Nine antimicrobial agents were tested by an agar dilution method. The respective percentages of resistance for 1981 and 1982 were as follows (%): cefoxitin, 8 and 10; moxalactam, 22 and 12; cefotaxime, 54 and 48; cefoperazone, 57 and 54; piperacillin, 12 and 7; clindamycin, 6 and 3; metronidazole, 0 and 0; chloramphenicol, 0 and 0; and tetracycline, 63 and 59. Regional differences in resistance rates were found. Declines in resistance to moxalactam, piperacillin, and clindamycin were noted at the participating hospitals. An outbreak of cefoxitin resistance was noted at the Tufts New England Medical Center, where the rate increased from 14 to 30%. The various species of the B. fragilis group had differing patterns of resistance; B. fragilis was the most susceptible species. Significant cross resistance among the beta-lactam agents was found. These data indicate the need to determine the susceptibility patterns of the B. fragilis group organisms within each hospital.

The in vitro activity of cefmetazole versus that of other antimicrobial drugs was assessed against 374 clinical isolates of Bacteroides spp., Clostridium spp., and anaerobic gram-positive cocci. Compared with cefoxitin, cefmetazole showed good activity against Bacteroides fragilis, other Bacteroides species, and anaerobic cocci. It was somewhat less active than cefoxitin against Bacteroides thetaiotaomicron, B. ovatus, B. distasonis, and B. vulgatus and somewhat more active against Clostridium spp.