Search

Introduction: With an increase in the incidence of Staphylococcus aureus infections in the healthcare settings and in the community, trimethoprim/sulfamethoxazole (TMP/SMX) has been suggested as a convenient treatment option. However, the appropriate dosage regimen of TMP/SMX is unclear. Objective: This study aimed to examine the pharmacokinetics/pharmacodynamics (PK/PD) of TMP/SMX against S. aureus using a neutropenic murine thigh infection model. Methods: Five S. aureus isolates with TMP/SMX (1:5 fixed ratio) minimum inhibitory concentrations (MICs) of 0.032–64 μg/mL were tested. The antimicrobial efficacy of TMP/SMX (1–689 mg/kg/day: dose shown as SMX dosage) was calculated as the change in bacterial density after 24 h of treatment. The plasma concentrations of TMP/SMX were detected using high-performance liquid chromatography. Results: After TMP/SMX single dose (130 mg/kg), the half-life, area under the blood concentration curve (AUC0–∞), and the protein binding ratio of SMX were 1.5 h, 718.2 μg h/mL, and 73.0 ± 8.3%, respectively. The free AUC/MIC and free %time (%T) above the MIC of SMX were better correlated with the in vivo antimicrobial activity than Cmax/MIC (free AUC/MIC, R2 = 0.69; free %T > MIC, R2 = 0.71; free Cmax/MIC, R2 = 0.53). The distributed doses (2–3 times per day) of TMP/SMX (130, 260, and 390 mg/kg/day) showed higher antimicrobial activity than the single dosage. However, TMP/SMX did not show its antimicrobial activity at T > MIC. Conclusions: The TMP/SMX treatment demonstrated that the free AUC/MIC of SMX was the better predictor of the PK/PD index of TMP/SMX.

Previous clinical studies have showed the clinical benefits of the initiation of treatment with a daptomycin (DAP) loading dose, but only a few studies have evaluated its antimicrobial benefits. We evaluated the efficacy of a DAP loading dose against methicillin-resistant Staphylococcus aureus (MRSA) infections in a neutropenic murine thigh infection model. Three MRSA isolates (DAP MIC: 0.5, 1, and 2 mg/L) were tested. Four DAP regimens simulating human concentration-time profiles, i.e., (i) day 1: 8 mg/kg and day 2: 6 mg/kg, (ii) days 1 and 2: 6 mg/kg/day, (iii) day 1: 8 mg/kg and day 2: 4 mg/kg, and (iv) days 1 and 2: 4 mg/kg/day, were administered to the mice. Efficacy was calculated as the change in bacterial density. DAP loading-dose regimen iii showed greater antimicrobial activity against MRSA with MIC 1 mg/L than nonloading regimen iv (-3.10 ± 0.63 vs. -0.71 ± 0.34 log10 CFU; p < 0.01). Loading-dose regimen iii achieved greater log10 CFU changes than nonloading regimen ii, while the total DAP dose for 2 days was the same (-3.10 ± 0.63 vs. -1.46 ± 0.48 log10 CFU; p < 0.05). DAP loading-dose regimen iii showed enhanced antimicrobial activity against MRSA with DAP MIC 0.5 mg/L when compared with nonloading regimen iv. However, loading-dose regimens i and iii did not reduce bacterial density for MRSA with DAP MIC 2 mg/L. Our data suggest that a DAP loading-dose regimen would be an advantageous procedure for patients infected with MRSA with DAP MIC ≤1 mg/L.

Background: Reports of Pseudomonas aeruginosa with high antimicrobial resistance have steadily emerged, threatening the utility of a mainstay in antipseudomonal therapy. This study evaluated the antimicrobial activities of various combination therapies against P. aeruginosa with high antimicrobial resistance, including multidrug-resistant P. aeruginosa (MDRP) using an in vitro and in vivo study. Methods: We evaluated 24 combination therapies, including colistin, aztreonam, meropenem, ceftazidime, ciprofloxacin, amikacin, rifampicin, arbekacin and piperacillin against 15 MDRP isolates detected at Aichi Medical University Hospital with the break-point checkerboard method. Based on the results of the in vitro study, we evaluated antimicrobial activity against highly antimicrobial-resistant P. aeruginosa with an in vivo murine thigh infection model. Results: The combination regimens including colistin and aztreonam showed higher antimicrobial activity against the 15 MDRP isolates. In the in vivo study, the high-dose colistin monotherapy (16 mg/kg every 12 h) achieved greater log10 CFU changes than the normal-dose colistin regimen (8 mg/kg every 12 h) against 5 P. aeruginosa isolates, including 2 MDRP isolates (p < 0.05). Aztreonam monotherapy (400 mg every 8 h) yielded bacterial densities similar to untreated control mice for the MDRP isolate evaluated. The combination therapy with a higher dose of colistin had superior antimicrobial activity against 5 P. aeruginosa with colistin (MIC 0.5 μg/ml) and aztreonam (MIC ≥128 μg/ml) than colistin monotherapy. Conclusion: The data suggest that the combination treatment of colistin and aztreonam could be the most useful for treating highly resistant P. aeruginosa with a higher susceptibility to colistin, including MDRP infections.

Background: Telithromycin is one of the ketolides, characterised by a 3-keto group instead of L-cladinose and a C11–C12 carbamate link by an alkyl chain to a pyridinum and imidazolium ring side chain. We evaluated in vitro and in vivo antibacterial activities of telithromycin against gynaecological pathogens. Methods: In the vitro study, the antibacterial activity of telithromycin against 180 isolates (isolated in the year 2000) of Streptococcus agalactiae (n = 33), Enterococcus faecalis (n = 22), Neisseria gonorrhoeae (n = 30), Peptostreptococcus anaerobius (n = 20), Finegoldia magna (n = 20), Bacteroides fragilis (n = 25) and Prevotella bivia (n = 30) was compared with that of erythromycin A, clarithromycin, azithromycin, ampicillin and levofloxacin. In the in vivo study, the efficacy of telithromycin was evaluated using experimental intra-abdominal abscesses in mice caused by B. fragilis (minimum inhibitory concentration of telithromycin 0.5 mg/l). Results: In the in vitro study, telithromycin inhibited more than 50% of clinical isolates of S. agalactiae, E. faecalis, N. gonorrhoeae, P. anaerobius, F. magna, B. fragilis and P. bivia at concentrations of 0.016, 0.063, 0.063, 0.032, 0.032, 0.5 and 0.25 mg/l, respectively. Telithromycin inhibited more than 90% of these clinical isolates at concentrations of 0.016, 4, 0.125, 0.063, 0.063, 4 and 1 mg/l, respectively. In the in vivo study, telithromycin inhibited abscess formation and significantly decreased viable cell counts in abscesses in comparison with the untreated group. Conclusions: These in vitro and in vivo antibacterial activities suggest that telithromycin could be a potential candidate for the treatment of bacterial infections complicated by chlamydial infection.

Biapenem is a new injectable carbapenem antibiotic which has favorable pharmacokinetic properties, and is stable to hydrolysis by dehydropeptidase I. Biapenem inhibited more than 90% of clinical isolates of Streptococcus agalactiae, Escherichia coli, Peptostreptococcus magnus, Bacteroides fragilis and Prevotella bivia at the concentration of 3.13 mg/l. The MIC90 of biapenem against Pseudomonas aeruginosa was lower than that of panipenem, equivalent to that of imipenem, and greater than that of meropenem. The in vivo efficacy of biapenem was evaluated using the experimental infection model of uterine endometritis. The accumulation of neutrophils in the uterus in the biapenem- treated group was less marked than in the nontreated group, as well as bacteriological response. These results suggest that the new antimicrobial agent biapenem might be useful for the treatment of polymicrobial infections in the fields of obstetrics and gynecology.

Prevotella bivia is common in pelvic inflammatory diseases. Parenteral antimicrobial agents have been widely used against those infections. We investigated the bactericidal activities of three cephalosporins, i.e. cefluprenam (CFLP), ceftazidime (CAZ) and cefotaxime (CTX) and of two other antimicrobial agents, i.e. clindamycin (CLDM) and imipenem (IPM) against P. bivia. We also investigated the in vitro morphological changes induced by these agents in P. bivia. Cephalosporins exhibited bactericidal activities against P. bivia and induced time- and concentration-dependent morphological changes in P. bivia (filamentation). CLDM and IPM also had bactericidal activities, but induced different morphologic alterations: formation of spheroblasts and lysis. These results confirm the fact that each antimicrobial agent has characteristic aspects.

S-1090 is a new synthetic, nonesterified, oral cephalosporin with a broad spectrum of antibacterial activity. The activities of S-1090 against the causative organisms in the fields of obstetrics and gynecology are superior to those of the currently prescribed oral cephems, cefdinir, cefpodoxime, and cefaclor. The in vivo efficacy of S-1090 was evaluated using uterine endometritis of model rats. The accumulation of neutrophils in the uterus in the S-1090-treated group was milder than that in the nontreated group, and the same was true for the bacteriological response. S-1090 is a promising oral cephalosporin antibiotic for the treatment of infections in the fields of obstetrics and gynecology.

Polymicrobial infections with aerobes and anaerobes are common in female genital tract infections. We evaluated the efficacy of an injectable new quinolone, pazufloxacin, using a uterine endometritis model. Rats were infected with a mixed inoculation of Escherichia coli plus Bacteroides fragilis (MIC of pazufloxacin and ceftazidime: E. coli: 0.05 and 1.56 µg/ml, respectively, B. fragilis: 3.13 and 3.13 µg/ml, respectively). After inoculating 107 cfu/rat of each organism, pazufloxacin or ceftazidime (10 or 20 mg/kg, respectively, i.v., b.i.d., 3 days) was administered and compared with the nontreated group. The viable cell counts of the uterine corpus and uterine cervix in pazufloxacin-treated and ceftazidime-treated groups were decreased, compared with the nontreated group. The viable cell counts of the adnexa in the pazufloxacin-treated group were significantly decreased, compared with the ceftazidime-treated group. These results suggest that pazufloxacin would be useful for the treatment of polymicrobial infections, especially adnexitis.

The bacteriological epidemiology of bacterial vaginosis (BV) and the efficacy of vaginal or oral treatment of BV with clindamycin (CLDM) were investigated. The epidemiology of BV was investigated in 100 symptomatic women before CLDM therapy. Two groups consisting of 50 patients each with the diagnosis of symptomatic BV were treated with either oral administration of 450 mg CLDM three times daily or 2% CLDM phosphate in vaginal cream (self-made) 5 g once a day, for 7 days. There was no significant difference in efficacy among vaginal and oral therapies with CLDM. Vulvovaginal irritation occurred in 3 patients orally treated and in 1 patient vaginally treated. Gastrointestinal disturbances were observed in 4 orally treated patients. A slight abnormal elevation of the glutamine-oxaloacetic transaminase level was also found in 1 patient orally treated. Since there were no statistically significant differences in efficacy rates between vaginal and oral CLDM treatments, we favor vaginal treatment of BV, based on less adverse effects.

To evaluate in vivo efficacy of macrolides; erythromycin (EM) and clarithromycin (CAM), in the different treatment schedules of Chlamydia trachomatis uterine cervicitis im women. Cervical C. trachomatis was detected by the polymerase chain reaction. EM was orally administered to 8, 15 and 18 Japanese patients, at a dosage of 600 mg, t.i.d. for 5, 7 and 14 days, respectively. CAM was orally administered to 10, 26 and 19 Japanese patients at a dosage of 400 mg, b.i.d. for 5, 7 and 14 days, respectively. The eradication rate and the recurrence rate in the different treatment schedules of C. trachomatis were evaluated. The eradication rates after 5, 7 or 14 days of treatment with EM were 1/8, 8/15 or 13/18, respectively. The recurrence rates after 5, 7 or 14 days of treatment with EM were 1/1, 3/8 or 2/13, respectively. On the other hand, the eradication rates after 5, 7 or 14 days of treatment with CAM were 5/10, 26/26 or 19/19, respectively. The recurrence rates after 5, 7 or 14 days of treatment with CAM were 3/5, 0/26 or 0/19, respectively. A 7-day treatment with CAM would be adequate and effective for C. trachomatis uterine cervicitis.