Bactericidal activities of LB20304, a new fluoroquinolone

The time-kill curves of LB20304, a novel fluoroquinolone that has potent antibacterial activity against gram-positve and gram-negative bacteria, were calculated at the concentration of 1/4-, 1/2-, 1-, 2- and 4-times the MIC againstStaphylococcus aureus 77, Escherichia coli, 3739E,Pseudomonas aeruginosa 1912E. The bactericidal activity of LB20304 for these strains was very rapid and comparable to that of ciprofloxacin. LB20304 produced a decrease in the log₁₀ CFU per milliliter of ≥3 within 2 h at 4-times the MIC for all strains and consitently prevented regrowth of bacteria after 24 h of incubation. The MBCs (Minimal Bactericidal Concentration) of LB20304 against test organisms were equal to or at most four-times higher than the MICs.     

Factors affectingin vitro activity of LB20304, a new fluoroquinolone

LB20304 is a novel fluoroquinolone that exhibits a potent broad spectrum antibacterial activity against both gram-positve and gram-negative bacteria. The MICs (Minimal Inhibitory Concentration) of LB20304 were determined against both gram-positve and gram-negative bacteria under various conditions including several media, pHs, and inoculum concentrations. Thein vitro activity of LB20304 was not significantly affected by the changes in testing conditions such as components of media and inoculum concentrations, but it was slightly reduced by acid condition. The MICs and MBCs (Minimal Bactericidal Concentration) of LB20304 againstStaphylococcus aureus, Escherichia coli andPseudomonas aeruginosa were hardly affected by the presence of 50% human serum, mouse serum, guinea pig serum or horse serum, and the MBCs were equal to or at most four-times higher than the MICs. The activities of LB20304 were decreased by the presence of high concentraion of Mg⁺⁺ or human urine (pH, 5.5) in the test media. The frequencies of mutants resistant to LB20304 were similar to or lower than those found in ciprofloxacin and sparfloxacin.     

Bacterial resistance to LB20304, a new fluoroquinolone antibiotic

In vitro studies were conducted to determine the frequency rate of spontaneous resistance to LB20304 and to dertemine whether cross-resistance to other antimicrobial agents develops. In eight strains of bacteria, the frequency of mutation to LB20304 at the concentrations of four and eight times the minimal inhibitory concentration (MIC) ranged from less than 4.0×10^?10 to 2.2×10^?8. These results were similar to those found for other new fluoroquinolones. The development of stepwise resistance was determined by repeated subculture in broth in the presence of increasing concentration of the compounds. Exposure of bacteria to increasing concentrations of LB20304 resulted in the selection of organisms with higher MICs. There were 4-to 128-fold increases in the MIC of LB20304 for bacterial strains ofStaphylococcus aureus, Streptococcus pneumoniae, Escherichia coli andPseudomonas aeruginosa. However, those strains, selected after repeated exposure were well within the susceptibility range for LB20304 except forPseudomonas aeruginosa. The resistant isolates selected with LB20304 showed cross-resistance when tested against ciprofloxacin andvice versa.     

Activity of nine fluoroquinolones against strains of Bordetella bronchiseptica

Thirty-two strains of Bordetella bronchiseptica were tested for their antimicrobial susceptibilities to nine fluoroquinolones. The most active agents were fleroxacin, temafloxacin, ciprofloxacin (MIC₉₀ 1 μg/ml), ofloxacin, lomefloxacin and enoxacin (MIC₉₀ 2 μg/ml). Pefloxacin and norfloxacin were active only against 59.3 and 83.1%, respectively, of the strains tested, whereas rufloxacin lacked activity against all the strains of B. bronchiseptica tested.     

司帕沙星与其他5种抗菌药体外抗菌活性比较研究

测定了司帕沙星对临床分离的１９９ 株致病菌的体外抗菌活性并与氧氟沙星、环丙沙星、头孢唑啉、头孢噻肟、阿米卡星的抗菌活性进行比较。司帕沙星对革兰阳性菌的ＭＩＣ９０为０．１２５～０．５ｍ ｇ／Ｌ,对金葡球菌、化脓链球菌的抑菌率均为１００％ ,强于氧氟沙星、环丙沙星;对革兰阴性菌也具有良好的体外抗菌活性,与氧氟沙星、环丙沙星相似。不同细菌接种量和不同浓度血清对其抗菌活性无明显影响,仅在ｐＨ５．０ 时抗菌活性略有下降     

In vitro activities of the newly synthesised ER-2 against clinical isolates of Mycobacterium tuberculosis susceptible or resistant to antituberculosis drugs

Two hundred isolates of Mycobacterium tuberculosis were evaluated for their susceptibility to a newly synthesised quinolone derivative, ER-2, compared with ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin. ER-2 and moxifloxacin showed the greatest activity [MIC for 90% of strains tested (MIC₉₀) = 0.5 μg/mL], although levofloxacin and ciprofloxacin showed good activity with an MIC₉₀ of 1 μg/mL. More importantly, ER-2 showed excellent activity against M. tuberculosis H37Rv both in the lungs and spleen of mice, indicating the potential therapeutic value of ER-2 against M. tuberculosis.     

In vitro andin vivo evaluations of LB10517, a novel parenteral broad-spectrum cephalosporin

Thein vitro activity of LB10517, a new catechol-substituted cephalosporin, was compared with those of E-1077, cefpirome and ceftazidime against 1034 clinical isolates collected in Japan. LB10517 showed a broad-spectrum antibacterial activity against a wide range of gram-positive and gram-negative bacteria including non-glucose fermenting rods,Pseudomonas aeruginosa. Against the methicillin-susceptible strains ofStaphylococcus aureus (MSSA) andStreptococcus pyogenes, the MIC₉₀ values of LB10517 which required to inhibit 90% of the strains were 3.13 μg/ml and 0.1 μ/ml, respectively. It was as active as E-1077 but more active than cefpirome and ceftazidime. Methicillin-resistant strains ofS. aureus (MRSA) andEnterococcus spp. were highly resistant to all the test compounds. LB10517 was highly active against most members of the familyEnterobacteriaceae, 90% of which were inhibited at a concentration of less than 0.78 μg/ml, except forEnterobacter cloacae (1.56 μg/ml) andSerratia marcescens (3.13 μg/ml). Its activity was comparable to those of E-1077 and cefpirome but it was greater than that of ceftazidime. AgainstPseudomonas aeruginosa, LB10517 showed the most potent antibacterial activity among the compounds tested. Ninety percent ofP. aeruginosa isolates were susceptible at the concentration of 0.39 μg/ml. Its activity was 32- to 128-fold higher than those of E-1077, cefpirome and ceftazidime. Against imipenem- or ofloxacinresistantP. aeruginosa, LB10517 with MIC₉₀s of 6.25 μg/ml and 3.13 μg/ml, respectively, showed 16-fold more potent activity than the other test compounds. LB10517 showed a relatively high plasma level and long plasma elimination half-life in rats (t_1/2(β), 52 min) and dogs (t_1/2(β), 103 min).     

The Role of Fluoroquinolones in Sexually Transmitted Diseases

The management of sexually transmitted diseases (STDs) has reached a new level in the era of antibiotic resistance and human immunodeficiency virus infection. To date, no single antimicrobial is capable of eradicating the commonly encountered STD pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Among the marketed fluoroquinolones, ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin all provide excellent in vitro activity (MIC₉₀ < 0.06 μg/ml) and excellent in vivo efficacy against N. gonorrhoeae, including multiply resistant isolates (penicillinase-producing N. gonorrhoeae and chromosomally mediated resistant N. gonorrhoeae). Ofloxacin is the only fluoroquinolone approved by the Food and Drug Administration for chlamydial infection. All of the quinolones lack reliable in vitro activity against Ureaplasma urealyticum, a cause of nongonococcal urethritis. Although limited data suggest the usefulness of ciprofloxacin and ofloxacin in the treatment of pelvic inflammatory disease, these drugs cannot currently be recommended for single-agent therapy. Haemophilus ducreyi infections, however, can be managed effectively with the fluoroquinolones. Although their role continues to evolve, this class of drugs cannot be used equally to treat all STDs, and notably, no quinolone to date inhibits T. pallidum.     

Comparative in vitro activity of enoxacin and other fluoro-quinolones against multi-resistant strains of Salmonella typhi

Summary

The in vitro activities of enoxacin, lomefloxacin, norfloxacin, ofloxacin, and pefloxacin against 274 strains of Salmonella typhi isolated from suspected typhoid fever patients (137 multi-resistant strains and 137 strains sensitive to chlor-amphenicol, ampicillin and/or co-trimoxazole) were determined using disk diffusion and agar dilution techniques. In vitro, enoxacin was active against all tested strains with a MIC₉₀ and inhibition zone size against multi-resistant strains of 0.12?mg/l and 34?mm diameter, respectively. Similar results were found with the other fluoroquinolones. Enoxacin and other fluoroquinolones may be the therapy of choice in cases of typhoid fever caused by organisms resistant to the standard therapy, chloramphenicol.     

Activity of eight fluoroquinolones against methicillin-resistant Staphylococcus aureus isolated from cutaneous infections

The in vitro susceptibility of methicillin-resistant Staphylococcus aureus to eight fluoroquinolones, norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, sparfloxacin and nadifloxacin, was evaluated. Methicillin-resistant S. aureus strains were isolated from 64 cutaneous infections from 1991 to 1993. Nadifloxacin exhibited the lowest MIC among all of the fluoroquinolones. In addition, there was no resistance to nadifloxacin. The MIC(50) of these drugs has been increasing in the past 3 years.     

Gatifloxacin‐1,2,3‐triazole‐isatin hybrids and their antimycobacterial activities

A series of gatifloxacin‐1,2,3‐triazole‐isatin hybrids 8a–l were designed, synthesized, and screened for their in vitro antimycobacterial activity as well as cytotoxicity toward Chinese Hamster Ovary (CHO) cells. The synthesized hybrids showed considerable activity against MTB H₃₇Rv and two MDR‐MTB strains with minimal inhibitory concentration (MIC) of 0.25–8 μg/ml, and the hybrid 8a (MIC_{MTB H37Rv}: 0.25 μg/ml and MIC_MDR‐MTB: 0.5 and 1 μg/ml) was found to be most active against the tested strains, which was not inferior to the parent gatifloxacin (MIC: 0.5, 0.25, and 0.5 μg/ml) against all three tested strains, and was ≥128‐fold more active than isoniazid (MIC: ≥64 μg/ml) and rifampicin (MIC: >128 μg/ml) against the two MDR‐MTB strains. Moreover, hybrid 8a (CC₅₀: 8.0 μg/ml) also displayed acceptable cytotoxicity toward CHO cells, and the selectivity index was 32. The structure–activity relationship and structure–cytotoxicity relationship were also enriched.     

Occurrence and ecological risk assessment of fluoroquinolone antibiotics in hospital waste of Lahore,Pakistan

In the present study, wastewater and sludge samples of two major hospitals of Lahore, Pakistan were analyzed by developing an HPLC-UV method for the possible occurrence of five frequently used fluoroquinolone antibiotics i.e. ofloxacin, ciprofloxacin, sparfloxacin, moxifloxacin and gemifloxacin. The highest detected concentration was for moxifloxacin in both wastewater (224 μg/L) and sludge samples (219 μg/kg. The highest concentration of ofloxacin, ciprofloxacin, sparfloxacin and gemifloxacin were found to be 66, 18, 58 and 0.2 μg/L respectively. Risk quotient (RQ) was also calculated based on maximum measured concentrations and the RQ values were very high particularly for ofloxacin and ciprofloxacin. The maximum RQ values for ofloxacin against Vibrio fisheri, Pseudomonas putida, fish, Daphnia, Green algae and Pseudokirchneriella subcapitata were 3300, 66,000, 124, 46, 3300 and 6000, respectively. In case of ciprofloxacin, RQ values were found to be 1750 and 3500 against green algae and Microcystis aeruginosa, respectively.     

Febrile neutropenia in a bone marrow transplantation unit

A total of 119 strains of coagulase-negative staphylococci isolated from clinical specimens were speciated and tested for sensitivity to methicillin and four fluoroquinolones (ciprofloxacin, sparfloxacin, levofloxacin and ofloxacin). Resistance to fluoroquinolones was significantly more common in Staphylococcus haemolyticus (43%) than in Staphylococcus epidermidis (11%). Methicillin-resistant strains of S. haemolyticus were more often resistant to ciprofloxacin than were methicillin-resistant strains of S. epidermidis (P < 0.05). Sparfloxacin was the most active against fluoroquinolone-sensitive strains, and levofloxacin was twice as active as ofloxacin. There was cross-resistance between the four fluoroquinolones. Levofloxacin was the most active against resistant strains, but MICs obtained for all the compounds seemed to be outside the clinically useful range for the treatment of systemic infections.     

6种氟喹诺酮类药物对临床分离金葡萄的抗菌活性比较

目的：观察临床分离金葡萄对6种氟喹诺酮类药物的耐药情况。方法：用琼脂稀释法测定诺氟沙星（NFLX）、氧氟沙星（OFLX）、氟罗沙星（FLRX）、环丙沙星（CPFX）、司帕沙星（SPFX）、托舒沙星（TFLX）6种2、3代氟喹诺桐类药物对成都地区155株临床分离金葡菌的体外抗菌活性。结果：金葡菌对6种药物的耐药率分别为诺氟沙星35.5%。氟罗沙星34.19%,环丙沙星27.75%,托舒沙星27.75% ,氧氟沙星25.81%,司帕沙星25.81%。结论：氟喹诺酮类药物的广泛应用已使细菌的耐药性明显增高,各药MIC90均超过16mg.L^-1,比以往文献报道的本地区金葡萄耐药性明显升高,提示要合理应用氟喹诺酮类药物,减少耐药菌株的增加。     

In vitro method for prediction of the phototoxic potentials of fluoroquinolones

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.     

Activity of gatifloxacin against strains resistant to ofloxacin and ciprofloxacin and its ability to select for less susceptible bacterial variants.

Gatifloxacin is an 8-methoxy fluoroquinolone. On quinolones, this side chain imparts increased activity against Gram-positive bacteria and enhanced killing. Gatifloxacin was tested against ofloxacin non-susceptible (ofloxacin MIC>2 mg/l) strains of Streptococcus pneumoniae (gatifloxacin MIC(90), 1 mg/l) and methicillin-resistant Staphylococcus aureus (MRSA, gatifloxacin MIC(90), 4 mg/l), and to ciprofloxacin non-susceptible (ciprofloxacin MIC>1 mg/l) strains of Escherichia coli (gatifloxacin MIC(90),>16 mg/l) and ciprofloxacin non-susceptible (ciprofloxacin MIC>0.06 mg/l) Neisseria gonorrhoeae (gatifloxacin MIC(50), 0.12 mg/l and MIC(90), 0.5 mg/l). Though gatifloxacin showed some reduced susceptibility to these populations, the MIC(50) and MIC(90) values suggest that gatifloxacin may be useful against pneumococci and some gonococcal strains not susceptible to other fluoroquinolones. Gatifloxacin did not select for less susceptible variants of MRSA and pneumococci, in contrast to the 10- to 100-fold higher selection frequencies with ciprofloxacin and ofloxacin. The single-step E. coli mutants selected by gatifloxacin and the comparator quinolones had quinolone MICs within the susceptible range. These data suggest that gatifloxacin use may hinder the development of quinolone-resistance, particularly in Gram-positive bacteria.     

Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin,linezolid or vancomycin,and strains with defined SCCmec types

Ceftobiprole is a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative pathogens including Pseudomonas aeruginosa. The aim of this study was to evaluate the activity of ceftobiprole against MRSA isolates with decreased susceptibility to daptomycin, linezolid or vancomycin as well as isolates from staphylococcal chromosome cassette mec (SCCmec) types I, II, III and IV. Overall, ceftobiprole demonstrated high potency against the 216 isolates tested, with MIC₅₀ and MIC₉₀ values (minimum inhibitory concentrations required to inhibit 50% and 90% of the isolates, respectively) of 1 mg/L and 2 mg/L (97.2% susceptible). The MIC₉₀ for ceftobiprole was 2 mg/L against the linezolid-non-susceptible, daptomycin-non-susceptible and vancomycin-intermediate (VISA and hVISA) subsets and was 1 mg/L against the vancomycin-resistant (VRSA) strains. The MIC_50/90 values for ceftobiprole were 2/4, 1/2, 2/2 and 1/1 mg/L against SCCmec types I, II, III and IV, respectively. SCCmec type I strains had the highest MICs, with six strains exhibiting a ceftobiprole MIC of 4 mg/L and 15 strains at 2 mg/L. Ceftobiprole demonstrated potent activity against MRSA, including subsets of isolates with reduced susceptibility to daptomycin, linezolid and vancomycin. The activity of ceftobiprole against these resistant phenotypes indicates that it may have clinical utility in the treatment of infections caused by multidrug-resistant S. aureus and across strains from prevalent SCCmec types.     

Surveillance of tigecycline activity tested against clinical isolates from a global (North America,Europe, Latin America and Asia-Pacific) collection (2016)

Tigecycline and comparators were tested by the reference broth microdilution method against 33 348 non-duplicate bacterial isolates collected prospectively in 2016 from medical centres in the Asia-Pacific (3443 isolates), Europe (13 530 isolates), Latin America (3327 isolates) and the USA (13 048 isolates). Among 7098 Staphylococcus aureus isolates tested, >99.9% were inhibited by ≤0.5?mg/L tigecycline (MIC_50/90, 0.06/0.12?mg/L), including >99.9% of methicillin-resistant S. aureus and 100.0% of methicillin-susceptible S. aureus. Tigecycline was slightly more active against Enterococcus faecium (MIC_50/90, 0.03/0.06?mg/L) compared with Enterococcus faecalis (MIC_50/90, 0.06/0.12?mg/L) and its activity was not adversely affected by vancomycin resistance when tested against these organisms. Tigecycline potency was comparable for Streptococcus pneumoniae (MIC_50/90, 0.03/0.06?mg/L), viridans group streptococci (MIC_50/90, 0.03/0.06?mg/L) and β-haemolytic streptococci (MIC_50/90, 0.06/0.06?mg/L) regardless of species and penicillin susceptibility. Tigecycline was active against Enterobacteriaceae (MIC_50/90, 0.25/1?mg/L; 97.8% inhibited at ≤2?mg/L) but was slightly less active against Enterobacteriaceae isolates expressing resistant phenotypes: carbapenem-resistant Enterobacteriaceae (MIC_50/90, 0.5/2?mg/L; 98.0% susceptible); multidrug-resistant (MIC_50/90, 0.5/2?mg/L; 93.1% susceptible); and extensively drug-resistant (MIC_50/90, 0.5/4?mg/L; 87.8% susceptible). Tigecycline inhibited 74.4% of 888 Acinetobacter baumannii isolates at ≤2?mg/L (MIC_50/90, 2/4?mg/L) and demonstrated good in vitro activity against Stenotrophomonas maltophilia (MIC_50/90, 1/2?mg/L; 90.6% inhibited at ≤2?mg/L) Tigecycline was active against Haemophilus influenzae (MIC_50/90, 0.12/0.25?mg/L) regardless of β-lactamase status. Tigecycline represents an important treatment option for resistant Gram-negative and Gram-positive bacterial infections.     

Design, synthesis, and docking studies of novel ofloxacin analogues as antimicrobial agents

A number of novel ofloxacin analogues were synthesized by modifying the carboxylic acid at C-6. To investigate the antimicrobial data on structural basis, in-silico docking studies of the tested compounds into the crystal structure of topoisomerase II using Autodock vina 4.0 program was performed in order to predict the affinity and orientation of the synthesized compounds at the activities. R ₂ values show good agreement with predicted binding affinities obtained by molecular docking studies. Also, it is verified by in-vitro antimicrobial screening, where all the compounds were most active against Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis. Among these compounds 3a, 3b, 3f showed good MIC (0.125?μg/ml).     

Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humour of patients by different topical application modes

Objectives: A prospective study was undertaken to determine the transcorneal penetration of three topically applied fluoroquinolones into aqueous humour. Methods: Two hundred and twenty-four patients undergoing cataract extraction received 0.3% ciprofloxacin, norfloxacin or ofloxacin eye drops by two different administration modes with different frequencies and intervals of application. At the beginning of cataract extraction (0.5–3 h after the last drop), 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using high-performance liquid chromatography. Results: Generally, topical ofloxacin and ciprofloxacin yielded aqueous humour levels higher than topical norfloxacin. The highest concentrations of all tested fluoroquinolones were measured after using an application mode, in which one drop was given every 15 min between 0600 hours and 0800 hours, prior to operation. When applied by this mode, ciprofloxacin achieved a mean aqueous level of 0.380 (±0.328) μg · ml⁻¹ (range 0.033–1.388 μg · ml⁻¹), norfloxacin 0.182 (0.118) μg · ml⁻¹ (range 0.038–0.480 μg · ml⁻¹) and ofloxacin 0.564 (0.372) μg · ml⁻¹ (range 0.064–1.455 μg · ml⁻¹). These mean concentrations were above the minimum inhibitory concentration (MIC₉₀), concentrations required for inhibition of 90% of pathogen strains in vitro of gram-negative bacteria, such as Proteus mirabilis and Escherichia coli. Therapeutic values above the MIC₉₀ of Staphylococcus epidermidis, the pathogen causing eye infections most frequently, were reached by 67.5% of patients after ofloxacin and by 41% after ciprofloxacin, but never after norfloxacin treatment. Conclusion: Of the currently available topical fluoroquinolones, ofloxacin achieved the highest aqueous humour concentration. This fluoroquinolone may be an useful ophthalmic agent for topical antibacterial management, but it does not seem to be prophylactically effective against Streptococcus pneumoniae or Pseudomonas aeruginosa. Received: 22 April 1997 / Accepted: 8 June 1997