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Efficacy of amoxycillin/clavulanic acid in experimental Bacteroides fragilis/Escherichia coli mixed infections.

The efficacy of amoxycillin/clavulanic acid was compared with those of metronidazole, cefuroxime, metronidazole/ampicillin, metronidazole/gentamicin and metronidazole/cefuroxime, in experimental mixed infections produced in mice by subcutaneous inoculation of amoxycillin-resistant strains of Bacteroides fragilis and Escherichia coli. The combination of metronidazole/ampicillin failed to inhibit the growth of E. coli, and exerted only a transient effect on the numbers of Bact. fragilis in the groin abscesses. In contrast, amoxycillin/clavulanic acid prevented the development of the infection, eliminating both organisms. Metronidazole and cefuroxime, alone and in combination, were less effective than amoxycillin/clavulanic acid in inhibiting the growth of the infecting organisms. These results demonstrate the clinical potential of amoxycillin/clavulanic acid in prophylaxis, or in the therapy of mixed aerobe/anaerobe infections.

Amoxicillin↗

Analysis of a capsular polysaccharide biosynthesis locus of Bacteroides fragilis.

A major clinical manifestation of infection with Bacteroides fragilis is the formation of intra-abdominal abscesses, which are induced by the capsular polysaccharides of this organism. Transposon mutagenesis was used to locate genes involved in the synthesis of capsular polysaccharides. A 24,454-bp region was sequenced and found to contain a 15,379-bp locus (designated wcf) with 16 open reading frames (ORFs) encoding products similar to those encoded by genes of other bacterial polysaccharide biosynthesis loci. Four genes encode products that are similar to enzymes involved in nucleotide sugar biosynthesis. Seven genes encode products that are similar to sugar transferases. Two gene products are similar to O-acetyltransferases, and two products are probably involved in polysaccharide transport and polymerization. The product of one ORF, WcfH, is similar to a set of deacetylases of the NodB family. Deletion mutants demonstrated that the wcf locus is necessary for the synthesis of polysaccharide B, one of the two capsular polysaccharides of B. fragilis 9343. The virulence of the polysaccharide B-deficient mutant was comparable to that of the wild type in terms of its ability to induce abscesses in a rat model of intra-abdominal infection.

Animals↗

In vivo efficacy of trovafloxacin against Bacteroides fragilis in mixed infection with either Escherichia coli or a vancomycin-resistant strain of Enterococcus faecium in an established-abscess murine model.

The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either Bacteroides fragilis-Escherichia coli-autoclaved cecal contents (ACC) or B. fragilis-vancomycin-resistant Enterococcus faecium (VREF)-ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of (99m)Tc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of B. fragilis-E. coli abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log(10) reduction in CFU/abscess in the respective B. fragilis and E. coli bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The C(max) was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with B. fragilis, while the killing of the anaerobe in the same combination was significantly less than in the E. coli combination (P < 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.

Abscess↗

Cigarette smoking increases the risk for subgingival infection with periodontal pathogens.

Cigarette smoking has been found to increase the risk for periodontitis. The present study examined the association between cigarette smoking and subgingival infection with periodontal pathogens to determine if smokers are more likely to be infected with certain periodontal pathogens than non-smokers. Self-reported data on 1,426 subjects, aged 25 to 74, from the Erie County Study were obtained including data on 798 subjects who were current or former smokers. Mean clinical attachment loss was used to estimate the severity of periodontal destruction. Subgingival infection with target periodontal pathogens was determined by indirect immunofluorescence microscopy. Smokers harbored significantly higher levels and were at significantly greater risk of infection with Bacteroides forsythus than non-smokers. Adjusting for disease severity, the risk of subgingival infection with B. forsythus in current smokers was 2.3 times that of former smokers or non-smokers. The relative risk of B. forsythus infection also increased 1.18 times for every category of smoking as the amount of smoking measured in packyears increased from very light to heavy. Adjusting for disease severity, Porphyromonas gingivalis was also more likely to subgingivally infect smokers than non-smokers; however, there was not a significantly higher relative risk for infection with this bacterium. The data from this study indicate that cigarette smoking increases the likelihood of subgingival infection with certain periodontal pathogens. This may partly explain the increased risk for periodontitis seen in smokers.

Adult↗

Direct and indirect pathogenicity of anaerobic bacteria in respiratory tract infections in children.

Bacteroides sp (Bacteroides melaninogenicus, Bacteroides oralis, and Bacteroides fragilis), peptostreptococci, and fusobacteria are important pathogens in respiratory tract infections (RTI). These organisms are often recovered mixed with other aerobic, facultative, and anaerobic bacteria. Evidence supporting their virulence is provided by studies showing their synergistic potentials in mixed infections and their increased virulence when encapsulated. A recent increase in numbers of beta-lactamase producing strains of anaerobic gram-negative bacteria in RTI has been associated with increased failure rates of penicillins in eradication of these infections. These infections include chronic otitis media, chronic sinusitis and mastoiditis, chronic recurrent tonsillitis, and lung abscesses. The pathogenicity of these organisms is apparent through their ability not only to survive penicillin therapy but also to protect penicillin susceptible pathogens from that drug. These direct and indirect virulence characteristics of anaerobic bacteria require the administration of appropriate antimicrobial therapy directed against all pathogens in mixed infections. The synergy that exists between different aerobic and anaerobic organisms in the respiratory tract is due to several pathogenic mechanisms. These mechanisms include the production of a capsule, which protects organisms from phagocytosis, and the production of beta-lactamase, which inactivates penicillins and first-generation cephalosporins. Both of these mechanisms enhance infection and induce complications. However, more work is necessary to prevent encapsulation and the production of enzymes. Data, thus far, indicate that there are therapeutic modalities that can be used to prevent these occurrences and eliminate many mixed RTI.

Animals↗

Antibody response following subcutaneous and intraperitoneal injection of Bacteroides fragilis in rabbits.

Intraperitoneal or subcutaneous injection of Bacteroides fragilis into rabbits resulted in IgM and IgG fluorescent antibody titers which did not differ significantly between the two groups of animals. Histologic studies revealed a typical abscess at the site of injection in subcutaneously injected animals while lung, liver, spleen and kidney sections from intraperitoneally injected animals showed normal tissue. The findings indicate that either intraperitoneal or subcutaneous injection can be used to study the serologic response in Bacteroides fragilis infections.

Abscess↗

The occurrence, virulence, and antimicrobial resistance of anaerobes in polymicrobial infections.

Polymicrobial aerobic/anaerobic bacterial infections occur frequently and have been documented in most anatomic sites in the body. The etiology of these infections is endogenous in that the normal microbial flora that colonize the various mucosal surfaces of the body can be isolated from these infections after trauma to these membranes allowing these organisms access to normally sterile sites. Subsequently, the organisms begin to proliferate, causing extensive tissue damage. These infections may spread to adjacent tissues or become loculated with abscess formation. In patients judged to have severe infection, surgery is often needed to debride the advancing spread of the infection, remove loculated pus, and reestablish sufficient blood flow to deliver appropriate antimicrobial agents to the infected site. Choice of antimicrobial agents should include agents with activity against both aerobes and anaerobes. Although a variety of anaerobes can be isolated from these infections, the Bacteroides fragilis group is the most clinically important group of anaerobes because of the production of virulence factors and the high incidence of beta-lactamase production. Against the various B. fragilis group species, metronidazole remains a very active agent, whereas resistance rates to clindamycin are high among the non-B. fragilis species. Because of the good activity of many cephalosporin/cephamycin agents against aerobic gram-negative bacteria and moderate to good activity against anaerobes, these compounds remain as broad-spectrum choices for use in therapy of mixed infections. The addition of beta-lactamase inhibitors (tazobactam, sulbactam, or clavulanate) to various beta-lactam agents has increased their antimicrobial spectrum against certain groups of aerobes, and particularly against beta-lactamase-producing anaerobes, including the B. fragilis group. The choice of single-agent therapy of mixed infections is ideally based on local data of susceptibility patterns of the various aerobes and anaerobes involved in these infections.

Anti-Bacterial Agents↗

In vitro susceptibility and in vivo efficacy of antimicrobials in the treatment of Bacteroides fragilis-Escherichia coli infection in mice.

Cefamandole, cefoxitin, cefotetan, ceftizoxime, imipenem plus cilastatin, and ampicillin plus sulbactam were compared in the eradication of subcutaneous abscess in mice caused by Bacteroides fragilis group organisms and Escherichia coli alone or in combination. The abscesses were examined 5 d after inoculation. B. fragilis group reached log10.1-11.0 organisms per abscess and E. coli log11.6-12.5. Imipenem plus cilastatin significantly reduced (in 6.9-10.6 logs) the number of E. coli and all members of B. fragilis group alone or in all combinations. Ampicillin plus sulbactam reduced the numbers of all B. fragilis group (in 4.2-7.2 logs) but was less effective against E. coli (reduction of 1.8-4.2 logs). Cefoxitin was effective in significantly reducing (in 4.9-6.2 logs) the number of E. coli and all members of B. fragilis group alone or in all combinations. Cefotetan was effective against B. fragilis (reduction of 5.1-6.6 logs) and E. coli alone or in combination but did not reduce the number of Bacteroides thetaiotaomicron, Bacteroides vulgatus, and Bacteroides ovatus. Ceftizoxime was effective against only B. ovatus (reduction of 3.7-5.8) and E. coli (reduction of 6.0-8.1 logs); it did not reduce the number of other organisms. Cefamandole was effective against only E. coli and was not effective against any member of the B. fragilis group. These in vivo data confirm the in vitro activity of these antimicrobials.

Abscess↗

Use of antibiotics for prevention of Bacteroides fragilis wound sepsis in rats.

A Bacteroides fragilis wound sepsis model was developed in rats. Topical and parenteral administration of clindamycin, chloramphenicol, and carbenicillin were used prophylactically to eradicate bacteria from contaminated wounds. Topical clindamycin prevented bacterial growth in 15 of 34 wounds, while topical chloramphenicol and carbenicillin were not effective. Clindamycin injected into the wound margins or at a distal site prevented bacterial growth in 16 of 18 wounds and in a lower dose prevented growth of 50 per cent of 12 wounds. These results support the clinical use of clindamycin for the prevention of Bacteroides wound infection.

Administration, Topical↗

Comparative study of clindamycin, imipenem, oxacillin and vancomycin in the infected granuloma pouch model.

In a rat granuloma pouch model, Staphylococcus aureus infection was treated with clindamycin, oxacillin or vancomycin and Bacteroides fragilis infection with clindamycin or imipenem. The model simulates a subcutaneous abscess and has the advantage of permitting frequent sampling of exudate for bacterial counts and antibiotic levels in the same animal. In staphylococcal infection all drugs reduced the bacterial counts in the infected pouch by 1-1.7 log, with a significant effect lasting for 3 h after the last injection. A 1.06-1.4 log reduction lasted for 24 h with clindamycin and oxacillin, but there was only an 0.3 log reduction at 24 h with vancomycin. The ratio of the drug concentration in the infected pouch to the MIC was highest with clindamycin (2.3) compared to oxacillin (1.6) and vancomycin (0.8). With Bact. fragilis infection the bacterial counts dropped 1.5 log at 3 h after the last injection with clindamycin and imipenem. At 24 h the counts were reduced 1.0 log with clindamycin and 0.5 log with imipenem. The ratios of pouch fluid concentration to MIC was 7.6 and 4.08 for imipenem and clindamycin, respectively, at 3 h, and 1.0 and 2.3 for imipenem and clindamycin at 24 h.

Animals↗

Prophylactic antibiotics in colon surgery.

One hundred twenty-three patients undergoing elective colon surgery were prospectively and randomly assigned to receive either three 1-g perioperative doses of intramuscular cephaloridine or three 1-g preoperative doses of both oral erythromycin base and neomycin sulfate. All patients had their bowels thoroughly cleansed mechanically. The groups were comparable in age and nutritional status. Eight wound infections occurred in the 65 patients receiving cephaloridine (12.3%) v one in the 58 receiving erythromycin and neomycin (1.7%). The difference was statistically significant. Eight of nine infected patients had only wound infections; the majority of cultures yielded Bacteroides fragilis. Serum and tissue antimicrobial concentrations were determined in the first 70 randomized patients at operation. Mean (+/- SD) cephaloridine levels were 14.7 +/- 10.2 and 10.5 +/- 10.0 mg/L in serum and tissue, respectively, compared with 1.98 +/- 1.58 and 0.699 +/- 1.146 mg/L for serum and tissue erythromycin levels.

Bacteroides Infections↗