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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.

Antimicrobial resistance, including plasmid-mediated resistance, among Bacteroides fragilis group species is well documented. A 5-year (1990-1994) prospective, eight-center survey of 3,177 clinical isolates of Bacteroides species was undertaken to review trends in resistance, using the breakpoints for full and intermediate susceptibility established by the National Committee for Clinical Laboratory Standards. No documented resistance to either metronidazole or chloramphenicol was found in this survey. Among B. fragilis isolates virtually no resistance was seen to imipenem, meropenem, ampicillin/sulbactam, piperacillin/tazobactam, or ticarcillin/clavulanate. Significant increases in resistance among B. fragilis isolates to cefotetan, ceftizoxime, and clindamycin (p < .01) were noted. Resistance to cefoxitin remained unchanged. Among the non-fragilis species of the B. fragilis group, there was virtually no resistance to imipenem, meropenem, chloramphenicol, or metronidazole. The three beta-lactamase inhibitors had increasing levels of resistance, although 95%-98% of strains were susceptible (p < .05). There was a significant decline in cefoxitin, cefmetazole, and clindamycin activity over time against these strains (p <.01). There was a significant (P < .001) increase in geometric mean minimum inhibitory concentration for most drugs and species tested from 1990 to 1994. Clusters in the eight institutions could not account for this rise in resistance. This survey demonstrates that rates of resistance of B. fragilis and non-fragilis species of B. fragilis group are increasing.

There is limited information regarding the correlation of anaerobic susceptibility testing and outcome in the treatment of Bacteroides fragilis infections. We retrospectively analyzed the clinical outcomes of B. fragilis infections in patients treated with cefoxitin; the analysis was blinded for susceptibility results. Isolates of B. fragilis were tested by multiple agar dilution methods, disk elution, and commercial broth microdilution methods. Of 19 patients analyzed, 11 were cured and 8 were treatment failures. No significant differences existed between the groups with respect to age, sex distribution, weight, APACHE II score, dose of cefoxitin, or bacteremia. Failure was associated with a longer cefoxitin dosing interval (P = 0.019), a longer duration of hospitalization (P = 0.038), and decreased duration of cefoxitin treatment (P = 0.05). Four agar dilution systems (brucella plus blood, Wilkins-Chalgren, Wilkins-Chalgren plus blood, brain heart infusion plus blood) and two broth systems (Wilkins-Chalgren microdilution and a commercial system [Micromedia; Beckman, Carlsbad, Calif.]) all demonstrated lower geometric mean MICs for isolates from the group of patients that could be cured. Only the commercial broth microdilution medium (Micromedia) demonstrated a significantly reduced geometric mean MIC (P = 0.056). By using a logistic regression analysis, the shorter cefoxitin dosing interval (P = 0.0004) and the lower geometric mean MIC (P = 0.0088) in the commercial broth microdilution system were shown to be independent predictors of treatment success. These data suggest that the time that the concentration of cefoxitin is over the MIC for B. fragilis may be an important predictor of treatment success.

A national survey of Bacteroides fragilis group was continued in 1989 for the ninth consecutive year. Seven hundred thirty-nine isolates of B fragilis group from eight centers were tested for susceptibility to 14 antimicrobials. Sulbactam and clavulanic acid, beta-lactamase inhibitors, were tested at a constant concentration of 8 micrograms/ml and 2 micrograms/ml, respectively. Sulbactam was also tested in a fixed ratio of 1:2. Imipenem, ampicillin+sulbactam, and ticarcillin+clavulanic acid had resistance of less than 1% at breakpoints of 8 micrograms/ml, 16 micrograms/ml, and 64 micrograms/ml, respectively. At 32 micrograms/ml, resistance to cefoxitin, cefotetan, ceftizoxime, and ceftriaxone were 4%, 25%, 26%, and 46%, respectively. Clindamycin resistance was 10% at a breakpoint of 4 micrograms/ml. No isolates were resistant to chloramphenicol or metronidazole. Resistance for five B fragilis species to cefoxitin, ceftizoxime, and cefotetan varied greatly among both species and participating institutions. The addition of a beta-lactamase inhibitor increased the potency of the beta-lactam drugs tested as combinations. This finding suggests that beta-lactamase production is the major resistance factor in members of the B fragilis group.

A continuing nationwide susceptibility survey of the Bacteroides fragilis group, begun in 1981, is being conducted at the New England Medical Center. Review of susceptibility testing in years 1986 through 1988 is reported here. Totals of 557 strains in 1986, 506 in 1987, and 534 in 1988 were obtained from seven centers in the United States. The most active beta-lactam drugs were beta-lactamase-inhibitor combinations ticarcillin-clavulanic acid, ampicillin-sulbactam, cefoperazone-sulbactam and the carbapenem imipenem. These drugs had virtually no resistance detected. Their rank order of activity was imipenem, ampicillin-sulbactam, ticarcillin-clavulanic acid, and cefoperazone-sulbactam, all with activity levels greater than cefoxitin or piperacillin, which, in turn, had activity levels greater than moxalactam, ceftizoxime, cefotetan, cefotaxime, cefoperazone, and ceftazidime. No metronidazole- or chloramphenicol-resistant isolates were found. Clindamycin resistance averaged 6% over the 3 years of testing. Ticarcillin-clavulanic acid, ampicillin-sulbactam, imipenem, and the non-beta-lactam drugs displayed uniform excellent activity against the five species of the B. fragilis group tested. The other beta-lactams displayed significant variability of activity among the various species.

A nationwide survey to monitor the susceptibility of the Bacteroides fragilis group, which began in 1981, was continued during 1987. In addition to the eleven drugs evaluated in 1986, sulbactam, a potent beta-lactamase inhibitor, was tested alone and in combination with ampicillin and cefoperazone. Imipenem, ampicillin/sulbactam, cefoperazone/sulbactam, and ticarcillin/clavulanic acid were the most active newer drugs tested, with less than 1% resistance rates. Chloramphenicol, metronidazole and clindamycin also had excellent activity with resistance rates of 0%, 0%, and 3% respectively. Resistance rates to cefoxitin remained stable at 8%. Ceftizoxime and cefotetan had resistance rates of 26% and 29%, respectively. Rates of resistance varied among different institutions and between the various species.

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.

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.

An improved understanding of the mechanisms of resistance and transfer in Bacteroides fragilis has been gained over the past decade. B. fragilis resistance to most penicillins is largely due to production of chromosomal beta-lactamases, although recent findings indicate these micro-organisms can acquire novel beta-lactamases, which can even inactivate imipenem. Several of the beta-lactamases of B. fragilis are transferable. Most of our understanding of transferable antimicrobial resistance in Bacteroides spp. has been gained through studies of the clindamycin-erythromycin resistance determinant found on pBFTM10. This resistance is encoded on a transposon and is widely distributed among the naturally occurring clindamycin-resistant isolates. Recent studies have shown that DNA can be transferred from Escherichia coli to B. fragilis, from one B. fragilis to another, and from B. fragilis back to E. coli. Data from a large survey in the United States indicate that susceptibility patterns of B. fragilis differ in each of the eight participating centres. Overall, piperacillin and cefoxitin have been found to be the most active beta-lactam agents.

A cefoxitin-resistant Bacteroides fragilis isolate, TAL 4170, which inactivates cefoxitin, was able to transfer beta-lactamase-mediated cefoxitin resistance to a susceptible B. fragilis recipient. Cefoxitin-resistant transconjugants acquired a new beta-lactamase with a pI of 8.1 and were able to inactivate cefoxitin and retransfer cefoxitin resistance. No plasmids were detected in the donor or transconjugants.

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.

Imipenem has excellent antimicrobial activity owing in part to beta-lactamase stability. We found that only 2 of over 350 Bacteroides fragilis group clinical isolates were resistant to imipenem, with an MIC of more than 16 micrograms/ml. These two isolates from the Tufts Anaerobe Laboratory (TAL) were resistant to all other beta-lactam agents tested. The organisms were able to inactivate imipenem in broth cultures and contained similar beta-lactamases that were able to hydrolyze carbapenems, cephamycins, cephalosporins, and penicillins. The molecular sizes of the beta-lactamases in TAL2480 and TAL3636 were estimated to be 44,000 daltons. The novel beta-lactamase contained Zn2+ as a cofactor. An additional factor contributing to resistance was determined. The outer membranes of these two organisms were found to limit free diffusion of the drugs into the periplasm. This novel beta-lactamase, associated with a barrier to drug permeation, resulted in high-grade beta-lactam drug resistance.

Antimicrobial resistance in Bacteroides from oral and colonic flora influences the selection of antimicrobial therapy to treat infections involving these organisms. An antimicrobial susceptibility study of 49 clinical isolates of oral bacteroides to 9 drugs revealed high resistance rates for penicillin 53%, for cefaclor 45%, and for tetracycline 27%, while there were low rates (less than 10%) with cefoxitin, piperacillin, clindamycin, chloramphenicol and metronidazole. Review of our U.S. nationwide survey of the susceptibility of colonic bacteroides (Bacteroides fragilis group) reveals low resistance to clindamycin, cefoxitin, piperacillin, imipenem, chloramphenicol and metronidazole. However, the identification of clindamycin, clindamycin, cefoxitin, piperacillin, imipenem and chloramphenicol resistant isolates is worrisome. The mechanism of resistance and the resistant transfer mechanism to the different classes of drugs in the oral and colonic bacteroides are reviewed.

The resistance of anaerobic bacteria to a number of antimicrobial agents has an impact on the selection of appropriate therapy for infections caused by these pathogens. Resistance to penicillin in Bacteroides fragilis has long been recognized. Most resistance is due to chromosomal beta-lactamases that are cephalosporinases. Two new enzymes that inactivate the ureidopenicillins and cefoxitin have been described in B. fragilis. The most common mechanisms of cefoxitin resistance is by the blocking of penetration of the drug into the periplasmic space. The transfer of beta-lactamase and penicillinase and of cefoxitin resistance has been demonstrated. Penicillin resistance in other Bacteroides is mediated by a penicillinase. Chloramphenicol resistance is mediated by a chloramphenicol acetyltransferase and by nitroreduction in anaerobic bacteria. Anaerobic bacteria are resistant to aminoglycosides because these organisms lack the oxidative transport system for intracellular drug accumulation. Metronidazole resistance, which is rarely encountered, is mediated by a decrease in nitroreduction of the compound to the active agent. Clindamycin-erythromycin resistance in B. fragilis is probably similar to macrolide-lincosamide-streptogramin resistance in aerobic bacteria. Two transfer factors, pBFTM10 and pBF4, which confer resistance to clindamycin have been described; the resistance determinant on them is widely distributed in nature. Tetracyline resistance in B. fragilis is mediated by a block in uptake of the drug. Transfer of tetracycline resistance is common; however, no transfer factor has been isolated. Transfer has been proposed to occur via a conjugal transposon. The special characteristics of the infected site influence the outcome of antimicrobial therapy, particularly in abscesses.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical doubling times of human solid tumors are reviewed. Methods are also described for estimating subclinical tumor doubling times, and these methods are applied to Wilms' tumor, choriocarcinoma, Burkitt's tumor, and breast cancer. Rapidly growing tumors are often responsive to therapy, and such complete responses are often quite durable. Slowly growing tumors respond less favorably to therapy, and responses are generally not durable. Rapidly growing tumors in advanced stages are similar in their response behavior to the slowly growing tumors. A strategy based on cell kinetics principles and tumor doubling time data is proposed for improving therapeutic results in responsive tumors. Data on clinical and subclinical tumor doubling times are used to distinguish early recurrences from late recurrences in a given tumor type. Early recurrences call for intensification of induction therapy, whereas late recurrences call for prolongation of consolidative therapy. This strategy may also apply in adjuvant therapy of slowly growing tumors.

The susceptibility and inoculum effect of 190 selected Bacteroides fragilis group isolates were determined with six beta-lactam antibiotics by two different methods: agar dilution and broth microdilution. The results were analysed by species within this group of pathogens. The evaluation showed that imipenem had superior activity and was very stable to increased inoculum concentration. Cefoxitin and piperacillin exhibited very good activity and very small inoculum effect; latamoxef showed stability to changes in the inoculum concentration but only intermediate activity; while ceftizoxime and cefoperazone exhibited a marked inoculum effect and relatively poor activity. Resistance among the species was as follows: B. distasonis greater than B. thetaiotaomicron greater than B. ovatus greater than B. fragilis. The inoculum effect was higher when tests were performed in broth rather than in agar. In general, the effect was more pronounced among B. ovatus and less among B. distasonis isolates.

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.

Knowledge of the mechanisms of antimicrobial resistance and resistance transfer in anaerobic bacteria has been gained over the past several years. There is widespread resistance to the beta-lactam antibiotics in the B. fragilis group of organisms and there is emerging penicillin resistance in other Bacteroides species. These resistances are usually mediated by chromosomal beta-lactamases. There have been two new beta-lactamases described in Bacteroides; a penicillinase which inactivates ureidopenicillins and another that inactivates cefoxitin. The transfer of the common beta-lactamase, penicillinase, and cefoxitin resistance has been documented in B. fragilis. The mechanism of tetracycline resistance in B. fragilis is the lack of accumulation of intracellular drug; the resistance is widespread in anaerobic bacteria and is seen in two-thirds of the B. fragilis strains. The transfer of tetracycline resistance is common, however, no transfer factor has yet been isolated. Clindamycin-erythromycin resistance in Bacteroides was first recognized in the mid-1970s and transferable resistance was described in 1979. The mechanism of resistance is probably similar to macrolide-lincosamide-streptinogramin-resistance seen in aerobic bacteria. Two clindamycin resistance transfer factors, pBFTM10 and pIP410 (pBF4) have been described. A common resistance determinant found both on plasmids and chromosomes is widely distributed in nature and it probably resides on a transposon. DNA homology studies indicate that there is more than one type of clindamycin resistance in Bacteroides; a newly recognized clindamycin resistance determinant is transferable. Local outbreaks of clindamycin resistance have been noted in the United States and in Europe. The susceptibility of Bacteroides in the United States in 1983 from a multi-center study reveals a 5% incidence of resistance in B. fragilis and 1% in Bacteroides species. The rate of clindamycin resistance has remained steady over the past three years in the Bacteroides fragilis group.

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.

The Bacteroides fragilis group of organisms includes the most clinically important anaerobic bacteria. Optimal therapy of infections in which these organisms are involved includes adequate and timely surgical drainage of all collections, debridement of necrotic tissue, optimal nutritional support, and administration of appropriate empiric antibiotics to cover both the aerobic and anaerobic bacterial components of these mixed infections. Special attention must be paid to the B. fragilis group because of its high rate of resistance to many of the commonly used antibiotics. Of the currently available beta-lactam antibiotics, piperacillin has the lowest rate of resistance. Successful antimicrobial agents include clindamycin, chloramphenicol, and metronidazole plus an aminoglycoside. Piperacillin, cefoxitin, and moxalactam can be used with an aminoglycoside or alone if no resistant organisms are revealed on culture and susceptibility testing. Beta-lactam-based regimens are potentially less toxic and may be less costly than those that contain one or more non-beta-lactam antibiotics.