Efficacy of telithromycin in the treatment of experimental Bacteroides fragilis intraabdominal abscess in the senescent mice.

The efficacy of telithromycin (HMR 3647), a new ketolide, in the treatment of experimental Bacteroides fragilis intraabdominal abscess in young and senescent mice was evaluated. Two different age groups of mice, young (2-3 months) and senescent (18-24 months) were used in this study. Telithromycin (50mg/kg/bid) was compared with clindamycin and metronidazole, both administered in 100 mg/kg/bid doses. Telithromycin cured the infection in 74% of the young and 67% of the old mice but this difference was not significant. Telithromycin efficacy was comparable to that of clindamycin which cured 82% of the young and 75% of the old, but was superior to the efficacy of metronidazole, which cured 61% of the young and 50% of the senescent mice. Young animals that were not cured by any of the three antibiotics showed decrease in the viable bacterial cell counts by two logs while the senescent mice had a one log difference. Serum, pus and tissue concentrations of telithromycin were five-fold higher in the old mice than in the young. Age by itself had no adverse effect on therapeutic outcome of any of the three antibiotics used.

Bacteroides fragilis-induced intra-abdominal abscess in an experimental model treated with telithromycin (HMR 3647).

BACKGROUND: Telithromycin (HMR 3647), a novel ketolide, is known to have activity against Bacteroides fragilis in vitro. METHODS: We tested this ketolide in an animal model of intra-abdominal abscess produced by intraperitoneal injection of B. fragilis with sterile feces and BaSO(4) mixture. Telithromycin was tested at two doses, 1. 25 and 2.0 mg/dose twice daily, and compared with clindamycin, cefotetan or metronidazole, all given at 2.0 mg/dose twice daily for 10 days. Absence of bacteria at the infected site was considered a cure and a positive culture considered a failure. RESULTS: The cure rate was 18% (5/28) on saline therapy, 74% (20/27) on telithromycin and 82% (23/28) on clindamycin, whereas it was 61% (17/28) on metronidazole and 59% (16/27) on cefotetan therapy. A high tissue antibiotic concentration (3-5 times the MIC) of telithromycin was found and this is presumably related to its superior efficacy. Delayed therapy initiated 7 days after infection instead of immediate therapy cured only 32% of the animals treated. The lower dose of telithromycin (1.25 mg/dose twice daily) was as effective as the higher dose (2 mg/dose twice daily). CONCLUSIONS: We found that telithromycin is as effective as clindamycin and more effective than metronidazole and cefotetan in this experimental model. These results suggest that telithromycin may be tested in future for the treatment of B. fragilis infections in humans.

Salmonella typhimurium-induced reactivation of latent HIV-1 in promonocytic U1 cells is inhibited by trovafloxacin.

We have previously reported that virulent Salmonella typhimurium induces replication of latent HIV-1 in U1 cells, via activation of tumor necrosis factor-alpha (TNF-alpha) production. In the present study, we show that Trovafloxacin, a new quinolone antibiotic, inhibits S. typhimurium-induced TNF-alpha production and HIV-1 replication. In addition, Trovafloxacin inhibits TNF-alpha-induced reactivation of latent HIV-1 in U1 cells. The concentrations of Trovafloxacin that inhibited HIV-1 replication are comparable to the plasma and tissue levels achieved by therapeutic dosage used in the treatment of bacterial infections. Therefore, Trovafloxacin is a potential candidate for adjunct therapy in HIV-1 infection.

Evaluation of trovafloxacin in the treatment of Klebsiella pneumoniae lung infection in tumour-bearing mice.

Trovafloxacin, a new trifluoroquinolone, was evaluated for its therapeutic efficacy against Klebsiella pneumoniae lung infection in tumour (P388 murine leukaemia cells)-bearing mice, treated with or without a chemotherapeutic agent, daunorubicin (DNR) and in mice without tumour. Its activity was compared with ciprofloxacin and cephazolin. The effect on therapeutic efficacy of the addition of recombinant granulocyte colony stimulating factor (rGCSF) was also examined. Our study showed that both quinolones successfully cured pneumonia owing to infection with K. pneumoniae in mice without tumours but that all antibiotics failed in tumour-bearing mice if DNR was withheld. Substantial differences were noted in DNR-treated tumour-bearing mice with infection-the cure rate with trovafloxacin was 91% whereas the cure rate with ciprofloxacin or cephazolin was 57%. Addition of rGCSF to ciprofloxacin did not substantially improve its efficacy (when assessed by protection against death owing to infection; the survival rate was 41%). Trovafloxacin cure rates ranged from 80 to 90% whether or not rGCSF was added to the treatment regimen. Our results suggest that prior cancer chemotherapy had no adverse effect on the therapeutic efficacy of trovafloxacin, and that trovafloxacin may be a promising therapeutic agent for treatment of bacterial infections in the presence of leucopenia.

Antibiotic prophylaxis in the surgical patient.

Antimicrobial selection for prophylaxis in surgery is based on the site of surgery, likely pathogen involved in addition to the in vitro efficacy, pharmacokinetics and the cost of the drugs used. For example, prophylactic agent in cardiovascular or orthopedic and skin and soft tissue surgery must cover against Staphylococcus aureus as well as the enterobacteriaceae; cephalosporins being adequate. On the other hand, any drug used in cases of urologic surgery must be excreted by the kidney in an active state and should also be active against E. coli, a common uropathogen such as any cephalosporins or penicillin. Drugs like macrolides and tetracyclines accumulate in the prostate and are good for prostate surgery by they are not excreted well by the kidney and therefore useless for urological prophylaxis. It is important to note that even treating minor infections in a neurosurgical patient, we must use an antibiotic that cross blood-brain barrier otherwise meningitis might develop. In cases of gastrointestinal tract, surgery on the colon and appendix requires special coverage against anaerobic bacteria especially Bacteroides fragilis. On the other hand surgery on the stomach, gall-bladder and upper two thirds of small intestine, it is adequate to use drugs to cover aerobic bacteria such as E. coli. Most studies show that a single most effective antibiotic is enough and it is unnecessary to use two or more drug combinations.

Outcome of primary empyema thoracis: therapeutic and microbiologic aspects.

BACKGROUND: This study was undertaken to determine whether all adult patients with primary empyema thoracis need decortication. METHODS: A management algorithm was developed and analyzed in a prospective, longitudinal, nonblinded study of 179 consecutive adult patients. The treatment options included thoracentesis, closed (tube) thoracostomy, image-guided catheter drainage, and decortication. We reviewed the outcomes of these procedures as they related to the pleural fluid cultures isolated and the antibiotic regimens used. RESULTS: Of the 179 patients, 20 had thoracentesis as the primary procedure, and 18 (90%) were cured. Ninety patients underwent closed thoracostomy as the primary procedure with a cure rate of 62% (56 patients) and a mortality rate of 11% (10 patients), and 24 patients required a secondary procedure. Seventy-six patients underwent decortication as either the primary or the secondary procedure with a cure rate of 88% (67 patients) and a mortality rate of 1.3% (1 patient); 8 patients required conversion to open thoracostomy. Hospital stay for decortication was 14+/-1 days and for closed thoracostomy, 17+/-1 days (p < 0.05). Decortication was necessary in 55% of patients with anaerobic infections and in 50% with aerobic infections. Clindamycin in combination with gentamicin sulfate was the most efficacious regimen with a success rate of 82% (51 of 62 patients); only 33% (17 of 52) were cured with penicillin. The overall mortality rate in this study was 6.7% (12 of 179 patients). CONCLUSIONS: Forty-two percent of patients with primary empyema thoracis ultimately require decortication. Decortication is more frequently necessary for anaerobic, tuberculous, staphylococcal, and pneumococcal infections. Although the overall mortality in this study was low, mortality remains high in elderly patients and patients with comorbid disease.

Posttraumatic empyema thoracis: a 24-year experience at a major trauma center.

The purpose of this paper is to review the outcome of patients with posttraumatic empyema thoracis. Between April 1972 and March 1996, the Division of Cardiothoracic Surgery at the King-Drew Medical Center managed or was consulted on 5,474 trauma patients (4,584 patients with penetrating injuries and 890 with blunt injuries) who were admitted emergently for thoracic and thoracoabdominal injuries and who underwent tube thoracostomy. Patients were not given routine prophylactic antibiotics merely because they had a chest tube placed. Based on our previous reports on thoracic trauma, our criteria for empiric antibiotic administration included (1) emergent or urgent thoracotomy, (2) soft-tissue destruction of the chest wall by shotgun injuries, (3) lung contusion with hemoptysis, (4) associated abdominal trauma requiring exploratory laparotomy, or (5) associated open long-bone fractures. Eighty-seven of these 5,474 patients developed posttraumatic empyema thoracis, for an incidence of 1.6%. These 87 patients were treated with tube thoracostomy, image-guided catheter drainage, or open thoracotomy with decortication. Seventy-nine of 87 patients (91%) were cured without conversion to open thoracostomy. Four patients required conversion to open thoracostomy, and there were three deaths. Even though a majority of our patients required decortication, successful management of posttraumatic empyema thoracis also was achieved with closed-tube thoracostomy or image-guided catheter drainage based on clinical and radiographic findings with appropriate patient selection. When thoracic empyema did occur in our group, Staphylococcus aureus was the most common microbe isolated, followed by anaerobic bacteria. In correlating microbiologic data with outcomes, S. aureus, especially methicillin-resistant S. aureus, was the most frequent cause of antibiotic failure. Because of the low incidence of posttraumatic empyema thoracis, we do not recommend routine antibiotic prophylaxis for all trauma patients who undergo closed-tube thoracostomy. A review of the role of tube thoracostomy, intrapleural fibrinolytic therapy, image-guided catheter drainage, video-assisted thoracoscopy, and open thoracotomy for the management of thoracic empyema is provided.

Efficacy of trovafloxacin for treatment of experimental Bacteroides infection in young and senescent mice.

We investigated the efficacy of trovafloxacin, a new quinolone, in comparison with that of clindamycin in the treatment of intra-abdominal abscesses caused by Bacteroides fragilis in young and senescent mice. The development of abscess formation, the number of viable organisms, and antibiotic concentrations were measured, and the values for young and old mice were compared. Trovafloxacin was well distributed to the tissues in both young and old animals. Although the pharmacokinetics and concentrations of trovafloxacin in serum were similar between young and old mice, the levels in tissue were higher in senescent mice than in young mice. Trovafloxacin therapy sterilized abscesses in 94% of young mice and in 73% of old mice, but this difference was not significant. This therapeutic response to trovafloxacin was similar to that seen with clindamycin. These results suggest that aging may not have any adverse effect on the therapeutic outcome for intra-abdominal abscesses caused by B. fragilis.

How many antibiotics are necessary to treat abdominal trauma victims?

We wanted to determine the value of single-versus multiple-antibiotic treatment in cases of penetrating abdominal trauma. Of 357 patients entered into a prospective, randomized, examiner-blinded study, 291 met all protocol criteria; 101 of these patients received cefoperazone alone, 95 were given ceftriaxone with metronidazole, and 95 were placed on metronidazole, gentamicin, and ampicillin. Aerobic and anaerobic bacterial cultures were obtained upon opening and closing the peritoneum. The three groups were found to be similar upon evaluation of key parameters, such as the median number of febrile days, morbidity, incisional wound infection, intra-abdominal abscess, septicemia, other infections, hospital stay, and death. Fifteen of 291 (5%) patients had infectious complications, and 12 (4.1%) developed noninfectious complications. There were six (2.1%) deaths, two in each antibiotic group. Noninfectious complications occurred more frequently in the triple-antibiotic group, which was statistically significant (P = 0.013). There were no therapeutic failures, and therefore, the routine usage of additional antibiotics to cover for enterococcus needs justification.

In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli.

The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.

Role of protein kinase beta isozyme in multidrug resistance in murine leukemia P388/ADR cells.

To define a role of protein kinase C (PKC) in multidrug resistance (MDR), we examined the influence of PKC isozyme specific antibodies delivered intracellularly, on drug sensitivity and drug accumulation in P388/ADR cells. Drug sensitive (P388) and drug resistant (P388/ADR) cells were permeabilized at 4 degrees C with L-lysolecithin and were incubated with rabbit anti-PKC, alpha, beta antibodies, or normal rabbit serum for 10 minutes at 37 degrees C. Daunorubicin (DNR) accumulation and drug sensitivity were studied by flow cytometry and MTT assay, respectively. Anti-PKC beta antibody partially corrected drug accumulation defect and completely reversed resistance to DNR. Anti-PKC alpha antibody had no effect on either parameter of MDR. These results suggest that PKC beta plays an important role in MDR in P388/ADR cells. Furthermore, the technique of intracellular delivery of antibodies provides a new approach to discern the role of PKC isoforms in multidrug resistance in various tumor cells.

Temporal patterns of radiographic infiltration in severely traumatized patients with and without adult respiratory distress syndrome.

We prospectively evaluated the patterns of pulmonary structural and functional changes in 100 consecutive surgical intensive care unit trauma patients who had (1) emergent major surgery, (2) a pelvic fracture, or (3) two or more major long bone fractures. For each patient, arterial blood gas measurements (ABGs), central venous pressure (CVP), pulmonary capillary occlusion pressure (PAOP), thoracic compliance, arterial oxygen tension/fraction of inspired oxygen (PAO2/FIO2), pulmonary venous admixture (Qs/Qt), and portable chest roentgenograms were sequentially tracked. The senior staff radiologist interpreted all chest roentgenograms. Pulmonary infiltration was quantitated in each of six fields using a scale ranging from 0 to 4, with 0 being no infiltration and 4 being the maximum. Adult respiratory distress syndrome (ARDS) was defined as follows: Qs/Qt > or = 20%, PAO2/FIO2 < 250 or both; dependence on mechanical ventilation for life support for > or = 24 hours; PAOP or CVP or both < 20 mm Hg; and thoracic compliance < 50 mL/cm H2O. Time zero (T0) the time of onset of ARDS, was defined as the time these criteria were met. Eighty-three of 100 study group patients had penetrating injuries, and 17 were admitted with blunt trauma. Fifty-one of 100 patients developed ARDS: 36 of 51 died. Only 4 of 49 (8%) patients without ARDS died. The injured lungs of patients with and without ARDS had similar amounts of infiltration over most measured time intervals. The noninjured lungs of the ARDS patients, however, had significantly greater infiltration than those without ARDS at T0 and over subsequent time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo effects of rufloxacin and ciprofloxacin on T-cell subsets and tumor necrosis factor production in mice infected with Bacteroides fragilis.

We investigated the in vivo effects of rufloxacin and ciprofloxacin on T-cell subsets and tumor necrosis factor production in mice infected with Bacteroides fragilis. These quinolones did not alter the helper/suppressor ratio but did modulate the kinetics of tumor necrosis factor production in infected animals. This result correlated with the observed therapeutic efficacies of the quinolones.

Piperacillin monotherapy compared with metronidazole and gentamicin combination in penetrating abdominal trauma.

The therapeutic efficacy and safety of piperacillin (4.5 g, every 6 hours) were compared with combined gentamicin (80 mg, every 8 hours) and metronidazole (500 mg every 6 hours) therapy in 246 patients hospitalized for penetrating abdominal injuries. Sixty-five patients had penetrating injury of the colon, rectum, or terminal ileum. The overall clinical cure rate was about 94% in both treatment groups. Adverse clinical experiences or biochemical abnormalities required discontinuation of therapy in three patients on gentamicin/metronidazole and in no patients on piperacillin.

Effect of rufloxacin on in-vitro proliferation and differentiation of human mononuclear cells.

We investigated the effects of rufloxacin, a new, long acting fluoroquinolone, on the growth and differentiation of human peripheral blood mononuclear cells (MNC) stimulated with T- and B-cell mitogenic agents. Rufloxacin inhibited 3H-thymidine incorporation into MNC stimulated with phytohaemagglutinin (PHA) and pokeweed mitogen (PWM) in a dose-dependent manner. The concentrations of rufloxacin required to inhibit 1/2 maximal proliferation of T- and B-cells were 62 and 33.5 mg/L respectively. Rufloxacin, at clinically achievable serum levels (less than 10 mg/L), was found not to inhibit PHA-induced T-cell differentiation as assessed by IL-2 production, IL-2 receptor expression and the expression of cell differentiation markers (CD4 and CD8). However, higher concentrations of rufloxacin (10 and 50 mg/L) markedly inhibited B-cell differentiation in-vitro as determined by the measurement of immunoglobulin production by MNC stimulated with PWM. The clinical relevance of our in-vitro findings remains to be elucidated.

Evaluation of temafloxacin in a rat model of intra-abdominal abscess.

The in-vitro activity of temafloxacin, a new fluoroquinolone, was evaluated in an experimental model of intra-abdominal abscess in rats. Mixed aerobic-anaerobic infection was induced by intraperitoneal implantation of gelatin capsules containing Bacteroides fragilis, Escherichia coli, and sterile rat faeces. Temafloxacin was highly active with a 90.9% cure rate in comparison with no treatment (no cures; P less than 0.0001), and as active as a combination of clindamycin and gentamicin (100% cure rate; P greater than 0.05). Temafloxacin (12 mg/dose) gave rise to serum concentrations that exceeded the MIC values of both microorganisms for at least 8 h.

Enoxacin therapy for severe pleuro-pulmonary infections.

Enoxacin, a new 6-fluoroquinolone known to be active in vitro against most common pulmonary pathogens, was evaluated in comparison with ceftazidime, a third generation cephalosporin proven to be effective in the treatment of gram negative pneumonias. Clinical and microbiologic responses to therapy were satisfactory and comparable in both antibiotic groups. Enoxacin could be an effective alternative choice in the treatment of lower respiratory tract infections caused by gram negative organisms.

Ciprofloxacin monotherapy for acute pelvic infections: a comparison with clindamycin plus gentamicin.

This prospective, randomized controlled study compared the efficacy and safety of ciprofloxacin alone versus a conventional two-drug regimen, clindamycin with gentamicin. The study group included 71 patients hospitalized for pelvic infections such as acute (N = 33) and chronic (N = 8) salpingitis, tubo-ovarian abscesses (N = 11), endometritis (N = 9), septic abortion (N = 3), and other categories (N = 7). Twenty-two of 35 patients on ciprofloxacin and 20 of 36 on clindamycin plus gentamicin had culturable pathogens: gonococci in 28, anaerobes in six, chlamydia in four, and associated pathogens in 19. Complete clinical and bacteriologic cure was achieved in 21 of 22 (95%) in the ciprofloxacin group and 19 of 20 (95%) in the clindamycin plus gentamicin group. The mean duration of intravenous/oral ciprofloxacin therapy was 3.7/7.2 days, and it was 3/6.6 days for clindamycin plus gentamicin. Ciprofloxacin, a new quinolone, appears to be safe as a single-drug therapy and was as effective as the combination of clindamycin plus gentamicin for the treatment of severe pelvic infections requiring hospitalization.

Enoxacin therapy for experimental pseudomonas keratitis.

Pseudomonas keratitis is difficult to treat and aminoglycosides, the drugs now used for this purpose, are not always effective. New drugs are thus needed to cure gentamicin resistant pseudomonas ocular infections. Enoxacin, a new quinolone, active in vitro against Pseudomonas aeruginosa, was evaluated in experimental ulcerative keratitis produced by a gentamicin resistant isolate of Pseudomonas aeruginosa in rabbits. Our study shows that enoxacin eye drops eliminated pseudomonas infection of the cornea and achieved therapeutic levels in the aqueous humor. Supplementation with parenterally given enoxacin augmented this effect. Enoxacin did not penetrate the vitreous. Enoxacin eye drops may be evaluated for their clinical usefulness in case of keratitis caused by Gram-negative bacilli.