In vivo efficacy of fluoroquinolones against systemic tularaemia infection in mice

OBJECTIVES: The in vivo efficacy of ciprofloxacin, gatifloxacin and moxifloxacin were assessed in an experimental Francisella tularensis Schu S4 infection in the BALB/c mouse model. METHODS: Mice were given 100 mg/kg of antibiotic by oral administration twice daily commencing at 6, 24 or 48 h post-exposure and continued for 14 days post-exposure. All mice were challenged subcutaneously with 1 x 10(6) cfu F. tularensis Schu S4 and observed for a period of 56 days. RESULTS: Treatment initiated 6 h post-exposure resulted in 94, 100 and 100% survival for ciprofloxacin, gatifloxacin and moxifloxacin, respectively. When treatment was delayed until 24 h post-exposure the survival rates were ciprofloxacin 67%, gatifloxacin 96% and moxifloxacin 100%. Treatment initiated at 48 h post-exposure resulted in a significant reduction in the survival rate of the ciprofloxacin-treated mice, with 0% survival compared with 84 and 62% for gatifloxacin and moxifloxacin, respectively. Non-treated infected control mice died within 96 h post-exposure. Dexamethasone given at day 42 for 7 days to suppress the animals' immune system caused relapse in all of the treatment groups. CONCLUSIONS: Both gatifloxacin and moxifloxacin were more effective at preventing mortality than ciprofloxacin and could be considered as alternative antibiotics in the treatment of systemic F. tularensis infection.     

Post-exposure prophylaxis of systemic anthrax in mice and treatment with fluoroquinolones

OBJECTIVES: To compare the fluoroquinolones gatifloxacin and moxifloxacin with ciprofloxacin for post-exposure prophylaxis of systemic anthrax in a BALB/c mouse model. METHODS: Treated mice and controls were inoculated subcutaneously with 5 x 10(4) spores/mouse of Bacillus anthracis Ames strain and observed for 37 days after challenge. Treated mice were given 100 mg/kg of antibiotic orally twice daily for 14 days, starting at various times post-challenge. RESULTS: Treatment starting 6 h post-challenge resulted in survival rates of 90%, 15% and 40% for gatifloxacin, moxifloxacin and ciprofloxacin, respectively. Treatment commencing 24 h post-challenge resulted in survival rates of 65%, 10% and 5%, respectively. Treatment starting more than 24 h after exposure had little effect on survival. CONCLUSIONS: Gatifloxacin appeared to be more effective than moxifloxacin or ciprofloxacin, at similar doses, for early post-exposure treatment of murine systemic anthrax. However, these results might be due to differences in potency or pharmacokinetic properties.     

A randomized, double-blind, multicenter comparison of gatifloxacin versus ciprofloxacin in the treatment of complicated urinary tract infection and pyelonephritis

BACKGROUND: Gatifloxacin is a fluoroquinolone antibiotic with a broad spectrum of in vitro and in vivo activity against the gram-negative and gram-positive pathogens frequently implicated in urinary tract infections (UTIs). OBJECTIVE: This study compared the clinical and bacteriologic efficacy and tolerability of gatifloxacin versus ciprofloxacin in adult patients with complicated UTIs or pyelonephritis. METHODS: In this double-blind, multicenter, randomized, comparative study, patients were treated with either gatifloxacin 400 mg once daily or ciprofloxacin 500 mg twice daily for 7 to 10 days. Bacteriologic eradication (by quantitative urine culture) and clinical efficacy rates were assessed at a test-of-cure visit (5 to 9 days and 4 to 11 days posttreatment, respectively) and at an extended follow-up visit (29-42 days and 25-50 days posttreatment, respectively). RESULTS: A total of 372 adults were randomized to treatment, 189 to gatifloxacin and 183 to ciprofloxacin. The most commonly isolated pretreatment pathogens (n = 292) were Escherichia coli (53%) and Klebsiella pneumoniae (13%). Pathogen eradication rates for complicated UTIs were 92% and 83% with gatifloxacin and ciprofloxacin, respectively (95% CI, -4.1% to 24.5%); for pyelonephritis, the respective rates were 92% and 85% (95% CI, -20% to 37%). Clinical response rates of >90% were observed in both treatment groups among patients with complicated UTIs as well as those with pyelonephritis. Sustained eradication rates were 76% (64/84) with gatifloxacin and 66% (52/79) with ciprofloxacin. Both drugs were well tolerated, with the most common adverse events in both treatment groups being nausea, dizziness, diarrhea, and vomiting. CONCLUSIONS: Gatifloxacin is comparable to ciprofloxacin based on clinical efficacy and bacteriologic eradication rates for the treatment of complicated UTIs or pyelonephri- tis and is associated with a low incidence of clinically significant adverse events.     

Antipneumococcal activity of DK-507k, a new quinolone, compared with the activities of 10 other agents

Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and clarithromycin against 113 penicillin-susceptible, 81 penicillin-intermediate, and 67 penicillin-resistant pneumococci (all quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of all quinolones against quinolone-susceptible strains (MIC at which 50% of isolates were inhibited [MIC50] and MIC90 of both, 0.06 and 0.125 microg/ml, respectively), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. MICs of beta-lactams and macrolides rose with those of penicillin G. Against 26 quinolone-resistant pneumococci with known resistance mechanisms, DK-507k and sitafloxacin were also the most active quinolones (MICs, 0.125 to 1.0 microg/ml), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Mutations in quinolone resistance-determining regions of quinolone-resistant strains were in the usual regions of the parC and gyrA genes. Time-kill testing showed that both DK-507k and sitafloxacin were bactericidal against all 12 quinolone-susceptible and -resistant strains tested at twice the MIC at 24 h. Serial broth passages in subinhibitory concentrations of 10 strains for a minimum of 14 days showed that development of resistant mutants (fourfold or greater increase in the original MIC) occurred most rapidly for ciprofloxacin, followed by moxifloxacin, DK-507k, gatifloxacin, sitafloxacin, and levofloxacin. All parent strains demonstrated a fourfold or greater increase in initial MIC in <50 days. MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and levofloxacin. Four strains were subcultured in subinhibitory concentrations of each drug for 50 days: MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Exposure to DK-507k and sitafloxacin resulted in mutations, mostly in gyrA.     

Mutant prevention concentration: comparison of fluoroquinolones and linezolid with Mycobacterium tuberculosis

OBJECTIVES: The mutant prevention concentration (MPC) has recently been defined to characterize the capacity for severely restricting the selection of resistant mutants during antibiotic treatment. We determined this parameter for ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin and linezolid in Mycobacterium tuberculosis clinical isolates in our setting. METHODS: We determined the antibiotic concentration that prevents the selection of resistant mutants following inoculation with a high mycobacteria inoculum on Middlebrook 7H11 plates with serial dilutions of the antibiotics in 224 M. tuberculosis isolates. RESULTS: Fifty percent of the strains exhibited values of MPC (MPC(50)) lower than 0.8, 0.6, 0.4, 0.4 and 0.6 mg/L for ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin and linezolid, respectively. If 90% of the strains are considered (MPC(90)), the values are seen to rise to 2, 1.8, 1, 1.2 and 1.2 mg/L, respectively. CONCLUSIONS: When we compare this parameter with the drug levels in serum and tissue, it can be seen that ciprofloxacin is the least useful of the fluoroquinolones studied, whereas moxifloxacin appears to be the most active. Linezolid exhibits excellent activity against this microorganism (MPC(90) 1.2 mg/L and AUC 140.3 mg.h/L) and this makes us consider that its usefulness in the treatment of this pathology should be thoroughly evaluated.     

Effect of fluoroquinolone treatment on growth of and toxin production by epidemic and nonepidemic clostridium difficile strains in the cecal contents of mice

Several recent outbreaks of Clostridium difficile-associated disease (CDAD) have been attributed to the emergence of an epidemic strain with increased resistance to fluoroquinolone antibiotics. Some clinical studies have suggested that fluoroquinolones with enhanced antianaerobic activity (i.e., gatifloxacin and moxifloxacin) may have a greater propensity to induce CDAD than ciprofloxacin and levofloxacin do. We examined the effects of subcutaneous fluoroquinolone treatment on in vitro growth of and toxin production by epidemic and nonepidemic C. difficile isolates in cecal contents of mice and evaluated the potential for these agents to inhibit fluoroquinolone-susceptible isolates during treatment. When C. difficile isolates were inoculated into cecal contents collected 2 days after the final antibiotic dose, gatifloxacin and moxifloxacin promoted significantly more growth and toxin production than ciprofloxacin and levofloxacin did. During treatment, gatifloxacin and moxifloxacin inhibited growth of fluoroquinolone-susceptible but not fluoroquinolone-resistant isolates. Ciprofloxacin and levofloxacin promoted growth of C. difficile when administered at higher doses (i.e., 20 times the human dose in mg/kg of body weight), and levofloxacin inhibited growth of fluoroquinolone-susceptible, but not fluoroquinolone-resistant, C. difficile isolates when administered in combination with ceftriaxone. Thus, fluoroquinolones with enhanced antianaerobic activity (i.e., gatifloxacin and moxifloxacin) promoted C. difficile growth to a greater extent than did ciprofloxacin and levofloxacin in this model. However, our findings suggest that fluoroquinolones may exert selective pressure favoring the emergence of epidemic fluoroquinolone-resistant C. difficile strains by inhibiting fluoroquinolone-susceptible but not fluoroquinolone-resistant isolates during treatment and that agents such as levofloxacin or ciprofloxacin can exert such selective pressure when administered in combination with antibiotics that disrupt the anaerobic microflora.     

In vitro and in vivo antibacterial activities of DK-507k, a novel fluoroquinolone

The antibacterial activities of DK-507k, a novel quinolone, were compared with those of other quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sitafloxacin, and garenoxacin (BMS284756). DK-507k was as active as sitafloxacin and was as active as or up to eightfold more active than gatifloxacin, moxifloxacin, and garenoxacin against Streptococcus pneumoniae, methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and coagulase-negative staphylococci. DK-507k was as active as or 4-fold more active than garenoxacin and 2- to 16-fold more active than gatifloxacin and moxifloxacin against ciprofloxacin-resistant strains of S. pneumoniae, including clinical isolates and in vitro-selected mutants with known mutations. DK-507k inhibited all ciprofloxacin-resistant strains of S. pneumoniae at 1 microg/ml. A time-kill assay with S. pneumoniae showed that DK-507k was more bactericidal than gatifloxacin and moxifloxacin. The activities of DK-507k against most members of the family Enterobacteriaceae were comparable to those of ciprofloxacin and equal to or up to 32-fold higher than those of gatifloxacin, levofloxacin, moxifloxacin, and garenoxacin. DK-507k was fourfold less active than sitafloxacin and ciprofloxacin against Pseudomonas aeruginosa, while it was two to four times more potent than levofloxacin, gatifloxacin, moxifloxacin, and garenoxacin against P. aeruginosa. In vivo, intravenous treatment with DK-507k was more effective than that with gatifloxacin and moxifloxacin against systemic infections caused by S. aureus, S. pneumoniae, and P. aeruginosa in mice. In a mouse model of pneumonia due to penicillin-resistant S. pneumoniae, DK-507k administered subcutaneously showed dose-dependent efficacy and eliminated the bacteria from the lungs, whereas gatifloxacin and moxifloxacin had no significant efficacy. Oral treatment with DK-507k was slightly more effective than that with ciprofloxacin in a rat model of foreign body-associated urinary tract infection caused by a P. aeruginosa isolate for which the MIC of DK-507k was fourfold higher than that of ciprofloxacin. Oral administration of DK-507k to rats achieved higher peak concentrations in serum and higher concentrations in cumulative urine than those achieved with ciprofloxacin. These data indicate the potential advantages of DK-507k over other quinolones for the treatment of a wide range of community-acquired infections.     

Efficacies of moxifloxacin, ciprofloxacin, and vancomycin against experimental endocarditis due to methicillin-resistant Staphylococcus aureus expressing various degrees of ciprofloxacin resistance

The new 8-methoxyquinolone moxifloxacin was tested against two ciprofloxacin-susceptible Staphylococcus aureus strains (strains P8 and COL) and two ciprofloxacin-resistant derivatives of strain P8 carrying a single grlA mutation (strain P8-4) and double grlA and gyrA mutations (strain P8-128). All strains were resistant to methicillin. The MICs of ciprofloxacin and moxifloxacin were 0.5 and 0.125 mg/liter, respectively, for P8; 0.25 and 0.125 mg/liter, respectively, for COL; 8 and 0.25 mg/liter, respectively, for P8-4; and >or=128 and 2 mg/liter, respectively, for P8-128. In vitro, the rate of spontaneous resistance of P8 and COL was 10(-7) on agar plates containing ciprofloxacin at two times the MIC, whereas it was 相似文献   

嗜麦芽窄食单胞菌体外药物敏感性研究

目的比较10种抗菌药物（莫西沙星、加替沙星、左氧氟沙星、环丙沙星、头孢哌酮-舒巴坦、替卡西林-克拉维酸、哌拉西林-三唑巴坦、头孢吡肟、头孢他啶、复方磺胺甲嗯唑）对临床分离嗜麦芽窄食单胞菌的体外抗菌活性。方法琼脂稀释法测定10种抗菌药物对来自北京3所医院的200株嗜麦芽窄食单胞菌的MIC值，用WHONET5．3软件进行药敏数据统计分析。结果200株菌对药物的敏感率排序为莫西沙星（84．5％）、加替沙星（79．5％）、左氧氟沙星（76％）、复方磺胺甲嗯唑（72．5％）、头孢哌酮-舒巴坦（41．5％）、替卡西林-克拉维酸（34％）、头孢他啶（23％）、环丙沙星（15％）、头孢吡肟（7％）和哌拉西林-三唑巴坦（4．5％）。结论新一代氟喹诺酮类药物如莫西沙星对嗜麦芽窄食单胞菌有较高的体外抗菌活性，是临床治疗嗜麦芽窄食单胞菌感染的较好选择。     

Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-tazobactam/amoxicillin-clavulanate

OBJECTIVES: Complicated skin and skin structure infections (cSSSIs), including diabetic foot infections (DFIs), are often polymicrobial, requiring combination or broad-spectrum therapy. Moxifloxacin, a broad-spectrum fluoroquinolone, is approved for cSSSI and can be administered by either intravenous (iv) or oral routes. To assess the efficacy of moxifloxacin for treating DFIs, we analysed a subset of patients with these infections who were enrolled in a prospective, double-blind study that compared the efficacy of moxifloxacin with piperacillin-tazobactam and amoxicillin-clavulanate. METHODS: Patients>or=18 years of age with a DFI requiring initial iv therapy were randomized to either moxifloxacin (400 mg/day) or piperacillin-tazobactam (3.0/0.375 g every 6 h) for at least 3 days followed by moxifloxacin (400 mg/day orally) or amoxicillin-clavulanate (800 mg every 12 h orally), if appropriate, for 7-14 days. DFI was usually defined as any foot infection plus a history of diabetes. Our primary efficacy outcome was the clinical response of the infection at test-of-cure (TOC), 10-42 days post-therapy. RESULTS: Among 617 patients enrolled in the original study, 78 with DFIs were evaluable for treatment efficacy. Clinical cure rates at TOC were similar for moxifloxacin and piperacillin-tazobactam/amoxicillin-clavulanate (68% versus 61%) for patients with investigator-defined infection (P=0.54). Overall pathogen eradication rates in the microbiologically-valid population were 69% versus 66% for moxifloxacin and comparator, respectively (P=1.00). CONCLUSIONS: Intravenous+/-oral moxifloxacin was as effective as iv piperacillin-tazobactam+/-amoxicillin-clavulanate in treating moderate-to-severe DFIs. Moxifloxacin may have potential as a monotherapy regimen for DFIs.     

Rapid in vivo screening of experimental drugs for tuberculosis using gamma interferon gene-disrupted mice

We have developed a rapid new in vivo method for screening experimental drugs for their activity against Mycobacterium tuberculosis by using the gamma interferon gene-disrupted (GKO) C57BL/6 mouse. Due to the rapid growth of the infection, statistical differences indicating positive efficacy of active compounds can be seen after only 8 days of treatment. To validate this model, several fluoroquinolones, including ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin, were tested in parallel.     

Comparative pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, trovafloxacin, and moxifloxacin after single oral administration in healthy volunteers

In an open, randomized, six-period crossover study, the pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin were compared after a single oral dose in 12 healthy volunteers (6 men and 6 women). The volunteers received 250 mg of ciprofloxacin, 400 mg of gatifloxacin, 600 mg of grepafloxacin, 500 mg of levofloxacin, 400 mg of moxifloxacin, and 200 mg of trovafloxacin. The concentrations of the six fluoroquinolones in serum and urine were measured by a validated high-performance liquid chromatography method. Blood and urine samples were collected before and at different time points up to 48 h after medication. Levofloxacin had the highest peak concentration (C(max), in micrograms per milliliter) (6.21+/-1.34), followed by moxifloxacin (4.34+/-1.61) and gatifloxacin (3.42+/-0.74). Elimination half-lives ranged from 12.12+/-3.93 h (grepafloxacin) to 5.37+/-0.82 h (ciprofloxacin). The total areas under the curve (AUC(tot), in microgram-hours per milliliter) for levofloxacin (44.8+/-4.4), moxifloxacin (39.3+/-5.35), and gatifloxacin (30+/-3.8) were significantly higher than that for ciprofloxacin (5.75+/-1.25). Calculated from a normalized dose of 200 mg, the highest C(max)s (in micrograms per milliliter) were observed for levofloxacin (2.48 +/-0.53), followed by moxifloxacin (2.17+/-0.81) and trovafloxacin (2.09+/-0.58). The highest AUC(tot) (in microgram-hours per milliliter) for a 200-mg dose were observed for moxifloxacin (19.7+/-2.67) and trovafloxacin (19.5+/-3.1); the lowest was observed for ciprofloxacin (4.6+/-1.0). No serious adverse event was observed during the study period. The five recently developed fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin) showed greater bioavailability, longer half-lives, and higher C(max)s than ciprofloxacin.     

Antianaerobic activity of a novel fluoroquinolone, WCK 771, compared to those of nine other agents

Agar dilution MIC methodology was used to compare the activity of WCK 771 with those of ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin, piperacillin, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 350 anaerobes. Overall, the MICs (in micrograms per milliliter) at which 50 and 90%, respectively, of the isolates tested were inhibited were as follows: WCK 771, 0.5 and 2.0; ciprofloxacin, 2.0 and 32.0; levofloxacin, 1.0 and 8.0; gatifloxacin, 0.5 and 4.0; moxifloxacin, 0.5 and 4.0; piperacillin, 2.0 and 64.0; piperacillin-tazobactam, < or =0.125 and 8.0; imipenem, 0.125 and 1.0; clindamycin, 0.125 and 16.0; and metronidazole, 1.0 and >16.0.     

Topical antibacterial therapy for mycobacterial keratitis: potential for surgical prophylaxis and treatment

BACKGROUND: Mycobacterium chelonae and Mycobacterium fortuitum are the 2 most commonly implicated species of nontuberculous mycobacteria in cases of bacterial keratitis. OBJECTIVES: This article summarizes available data on the in vitro antibacterial activity against M chelonae or M fortuitum of 2 agents-amikacin and clarithromycin-that have been used in the treatment of bacterial keratitis. In addition, the article reviews the in vitro activity of 5 commercially available topical ocular fluoro-quinolones (in order of availability, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin) that may have potential in the surgical prophylaxis and treatment of keratitis caused by M chelonae or M fortuitum. METHODS: A search of the English-language literature indexed on the MEDLINE, Life Sciences, EMBASE, BIOSIS, and Pharmaprojects databases from 1966 to October 7, 2003, was conducted using the terms Mycobacterium chelonae, Mycobacterium fortuitum, bacterial keratitis, topical antibiotic therapy, ocular infection-mycobacteria, and LASIK infections. Data on the minimum concentrations at which 90% of isolates were inhibited (MIC(90)s) were reviewed and compared. RESULTS: In the literature reviewed, the MIC(90) against M fortuitum was from 1 to 16 microg/mL for amikacin, from /=8 microg/mL for clarithromycin, from 0.1 to 1 microg/mL for ciprofloxacin, from 0.5 to 3.13 microg/mL for ofloxacin, and 相似文献   

Cytotoxicity of topical medications used for infection and inflammation control after cataract surgery in cultured corneal endothelial cells

Postoperative vision-threatening corneal edema sometimes occurs after eye surgery, and corneal endothelial damage may be caused or exacerbated by drug toxicity. A range of commercially available antibiotic and anti-inflammatory ophthalmic solutions used postoperatively, namely levofloxacin, moxifloxacin, gatifloxacin, cefmenoxime, diclofenac, bromfenac, pranoprofen, betamethasone, and fluoromethorone, were assessed by using human corneal endothelial cells (HCECs). Propylparaoxybenzoate and methylparaoxybenzoate were also examined. Cell survival after 48 h exposure to the drugs was evaluated using the WST assay. Cefmenoxime and betamethasone were the least toxic antibiotic and anti-inflammatory drug, respectively. Cell survival was concentration dependent and increased markedly to ≥ 80% with dilutions of 100-fold or more. Two preservatives seemed to cause minimal cytotoxicity among those tested. Antibiotic cytotoxicity to HCEC was ranked as cefmenoxime < levofloxacin = gatifloxacin < moxifloxacin, while the toxicity of anti-inflammatory drugs was dependent on benzalkonium chloride and polysorbate. These drugs are unlikely to cause HCEC damage at the concentrations used under the usual conditions. Preservatives are essential ingredients in ophthalmic solutions to control postoperative infection and inflammation and we should be aware of their toxicity as well as efficacy.     

Susceptibility of Mycobacterium tuberculosis strains to gatifloxacin and moxifloxacin by different methods

BACKGROUND: Considering the potentials of gatifloxacin and moxifloxacin in the treatment of tuberculosis, the present study was aimed to define resistance to both these drugs. METHODS: Fifty Mycobacterium tuberculosis isolates, consisting of 30 ofloxacin-susceptible and 20 ofloxacin-resistant strains, were tested for their susceptibility to gatifloxacin and moxifloxacin using different susceptibility testing methods, namely the absolute concentration method on Lowenstein-Jensen medium (LJ), the proportion susceptibility testing method (PST) on LJ and 7H11 agar media, and the BACTEC radiometric method. RESULT: The minimal inhibitory concentration (MIC) of gatifloxacin and moxifloxacin was 1 microg/ml by the absolute concentration method on LJ. In the PST method on LJ and 7H11, using a criterion of > or =1% growth as resistant, there was 100% agreement with the absolute concentration method at a concentration of 0.5 microg/ml for gatifloxacin, and 96% agreement with the BACTEC method at a concentration of 0.25 microg/ml. For moxifloxacin, results by the PST method showed 96% agreement with the absolute concentration method on LJ at a concentration of 1 microg/ml and 92% agreement at a concentration of 0.5 microg/ml for both the absolute concentration method on 7H11 and the BACTEC method. CONCLUSIONS: The MICs of gatifloxacin and moxifloxacin were much lower than the MICs of other quinolones like ofloxacin and ciprofloxacin. Additionally, these two drugs have shown a low mean MIC and low concentration as a definition of resistance, which might help in treating the patients with low levels of quinolone resistance.     

Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin and moxifloxacin in Streptococcus pneumoniae

The ability of sequential subcultures in subinhibitory concentrations of gemifloxacin, trovafloxacin, ciprofloxacin, gatifloxacin and moxifloxacin to select resistant mutants was studied in 16 pneumococci [eight with ciprofloxacin MICs (mg/L) 0.25-1; four with 8-16; four with 16-32]. Subculturing was done 50 times, or until mutants with elevated MICs (> or = 4 x) to the selecting drug emerged. Subculturing in gemifloxacin selected six resistant mutants (gemifloxacin MICs 2 mg/L); trovafloxacin selected nine (trovafloxacin MICs 2-4 mg/L); ciprofloxacin selected 11 (ciprofloxacin MICs 8-128 mg/L); gatifloxacin selected 13; and moxifloxacin selected 12 (gatifloxacin or moxifloxacin MICs 2-16 mg/L). DNA sequencing showed that most mutants had mutations in ParC at Ser-79 or Asp-83 and in GyrA at Ser-81 or Glu-85; some mutants also had mutations in ParE or GyrB. Some new mutations were found in ParE or GyrB that have not yet been reported; GyrB mutation might be associated with moxifloxacin resistance. Both DNA gyrase and topoisomerase IV were thought to be the target of gemifloxacin; gemifloxacin also selected mutants with single modifications in gyrA, parC or parE alone among derived mutants by repeated exposure to subinhibitory concentrations of fluoroquinolones. In the presence of reserpine, most mutants had lower MICs of ciprofloxacin and gemifloxacin (4-32 x), and gatifloxacin (4-8 x), suggesting an efflux mechanism; none had lower trovafloxacin and moxifloxacin MICs. All quinolones tested selected for resistance; judicious use and proper dosing will be necessary to avoid resistance selection of newer broad-spectrum fluoroquinolones.     

In vitro antibacterial activity of fluoroquinolones against Porphyromonas gingivalis strains

OBJECTIVES: The objective of the study was to evaluate the in vitro activity of ciprofloxacin, gatifloxacin and moxifloxacin against 16 Porphyromonas gingivalis strains. METHODS: MICs of the quinolones were established by Etest and the agar dilution technique. Experiments focused on determination of the spontaneous mutation rate and the induction of resistant strains, using 0.25-fold MIC of antibiotic. Fragments of gyrA and gyrB as well as of parC were sequenced. RESULTS: Moxifloxacin and gatifloxacin had very low MIC values. Subinhibitory concentrations of the fluoroquinolones rapidly induced mutations. The spontaneous mutation rate was strain- and quinolone-dependent; the lowest rate was encountered after moxifloxacin. The predicted serum concentrations of the quinolones were bactericidal to wild-type strains, but 100 mg/L of each tested quinolone was insufficient to kill a mutant exhibiting moderate resistance. Often the mutants exhibited high resistance to >/=32 mg/L. All these mutants bore a Ser-83-->Phe substitution in GyrA. CONCLUSIONS: DNA gyrase is the primary target of fluoroquinolones in P. gingivalis. In terms of the achievable level in the gingival fluid and the MICs, moxifloxacin might prevent the development of resistance and may be an alternative in the antibiotic treatment of P. gingivalis-associated periodontitis.     

In vivo efficacy of a new quinolone, DQ-113, against Streptococcus pneumoniae in a mouse model

DQ-113 is a new quinolone with potent activity against gram-positive pathogens. The in vivo activity of DQ-113 against Streptococcus pneumoniae was compared with those of gatifloxacin and ciprofloxacin in a mouse model. For this purpose, two strains of S. pneumoniae were used: penicillin-susceptible S. pneumoniae (PSSP) and penicillin-resistant S. pneumoniae (PRSP). The survival rates of mice infected with PSSP and PRSP at 14 days after infection were 80% in the DQ-113-treated group and 0 to 10% in the other three groups. In murine infections caused by PSSP, the 50% effective doses (ED50s) of DQ-113, gatifloxacin, and ciprofloxacin were 6.0, 41.3, and 131.6 mg/kg, respectively. Against PRSP-caused pneumonia in mice, the ED50s of DQ-113, gatifloxacin, and ciprofloxacin were 7.6, 64.7, and 125.9 mg/kg, respectively. Compared with the other drugs, DQ-113 showed excellent therapeutic efficacy and eradicated viable bacteria in both PSSP- and PRSP-infected mice. The means +/- standard errors of the means of viable bacterium counts in the lungs of gatifloxacin-treated, ciprofloxacin-treated, and untreated control mice infected with PSSP were 2.91 +/- 0.34, 3.13 +/- 0.48, and 3.86 +/- 0.80 log10 CFU/ml, respectively. The same counts in mice infected with PRSP treated with the same three agents were 6.57 +/- 0.99, 6.54 +/- 0.40, and 7.17 +/- 0.43 log10 CFU/ml, respectively. DQ-113 significantly decreased the number of viable bacteria in the lungs compared with gatifloxacin and ciprofloxacin. Of the drugs analyzed, the pharmacokinetic-pharmacodynamic parameter of area under the concentration-time curve (AUC)/MIC ratio for DQ-113 was significantly higher than those for gatifloxacin and ciprofloxacin. Our results suggest that DQ-113 has potent in vivo efficacy against both PSSP and PRSP.     

Determination of antibiotic efficacy against Bacillus anthracis in a mouse aerosol challenge model

An anthrax spore aerosol infection mouse model was developed as a first test of in vivo efficacy of antibiotics identified as active against Bacillus anthracis. Whole-body, 50% lethal dose (LD50) aerosol challenge doses in a range of 1.9x10(3) to 3.4x10(4) CFU with spores of the fully virulent Ames strain were established for three inbred and one outbred mouse strain (A/J, BALB/c, C57BL, and Swiss Webster). The BALB/c strain was further developed as a model for antibiotic efficacy. Time course microbiological examinations of tissue burdens in mice after challenge showed that spores could remain dormant in the lungs while vegetative cells disseminated to the mediastinal lymph nodes and then to the spleen, accompanied by bacteremia. For antibiotic efficacy studies, BALB/c mice were challenged with 50 to 100 LD50 of spores followed by intraperitoneal injection of either ciprofloxacin at 30 mg/kg of body weight (every 12 h [q12h]) or doxycycline at 40 mg/kg (q6h). A control group was treated with phosphate-buffered saline (PBS) q6h. Treatment was begun 24 h after challenge with groups of 10 mice for 14 or 21 days. The PBS-treated control mice all succumbed (10/10) to inhalation anthrax infection within 72 h. Sixty-day survival rates for ciprofloxacin and doxycycline-treated groups were 8/10 and 9/10, respectively, for 14-day treatment and 10/10 and 7/10 for 21-day treatment. Delayed treatment with ciprofloxacin initiated 36 and 48 h postexposure resulted in 80% survival and was statistically no different than early (24 h) postexposure treatment. Results using this mouse model correlate closely with clinical observations of inhalational anthrax in humans and with earlier antibiotic studies in the nonhuman primate inhalational anthrax model.