Related Articles

This study was undertaken to determine in vivo permeability coefficients for fluoroquinolones and to assess its correlation with the permeability derived using reported models in the literature. Further, the aim was to develop novel QSPR model to predict corneal permeability for fluoroquinolones and test its suitability on other training sets. The in vivo permeability coefficient was determined using cassette dosing (N-in-One) approach for nine fluoroquinolones (norfloxacin, ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin, sparfloxacin, pefloxacin, gatifloxacin, and moxifloxacin) in rabbits. The correlation between corneal permeability derived using in vivo studies with that derived from reported models was determined. Novel QSPR-based model was developed using in vivo corneal permeability along with other molecular descriptors. The suitability of developed model was tested on β-blockers (n = 15). The model showed better prediction of corneal permeability for fluoroquinolones (r2 > 0.9) as well as β-blockers (r2 > 0.6). The newly developed QSPR model based upon in vivo generated data was found suitable to predict corneal permeability for fluoroquinolones as well as other sets of compounds.

The in vitro activity of Q-35, an 8-methoxy fluoroquinolone, was compared with those of ofloxacin, ciprofloxacin, tosufloxacin, lomefloxacin, and sparfloxacin. The MICs of Q-35 for 90% of strains tested (MIC90s) of Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes were 0.2, 6.25, 0.2, 0.39, and 0.39 micrograms/ml, respectively. The activity of Q-35 was 4- to 16-fold greater than those of ofloxacin, ciprofloxacin and lomefloxacin but equal to those of tosufloxacin and sparfloxacin against these organisms. For 82 ciprofloxacin-resistant staphylococci (MIC90 = 100 micrograms/ml), Q-35 was the most active of the new quinolones tested (MIC90 = 6.25 micrograms/ml). The MIC90s of Q-35 against Escherichia coli, Enterobacter aerogenes, and Pseudomonas aeruginosa were 0.2, 0.78, and 12.5 micrograms/ml, respectively, and Q-35 was 2- to 16-fold less active than the other quinolones tested. Q-35 showed potent bactericidal activity and inhibited the supercoiling activity of DNA gyrase of S. aureus, E. coli, and P. aeruginosa.

The efficacy and safety of three oral fluoroquinolones (lomefloxacin, levofloxacin, and ciprofloxacin) for the treatment of chronic osteomyelitis were analyzed. Twenty-seven patients had documented infections with quinolone-sensitive organisms and received either lomefloxacin, levofloxacin, or ciprofloxacin. Levofloxacin was effective therapy for 9 of 15 (60%) patients. Lomefloxacin was effective therapy for five of seven (71%) patients, and ciprofloxacin was effective therapy for two of five patients (40%). Average follow-up was 11.8 months for patients who completed the course of therapy, and the average duration of therapy was 60.6 days. Gram-positive bacteria were isolated from 18 patients, and 11 patients were cured. Oral fluoroquinolones can be safe, effective therapy if they are given for a prolonged course as treatment for infections caused by susceptible gram-positive as well as gram-negative organisms and in combination with adequate surgical debridement.

Aeromonas hydrophila, an uncommon human pathogen, can cause invasive infections in immunocompromised individuals. As the fluoroquinolones have been shown to be active in vitro against mesophilic aeromonads and clinical experience with the use of fluoroquinolones to treat aeromonads infections is limited, the antimicrobial activities of five selected drugs (ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin, and moxifloxacin) against A. hydrophila were studied in vitro and in mice. The MICs of the fluoroquinolones (except lomefloxacin), cefotaxime, and minocycline for 90% of 64 clinical isolates of A. hydrophila tested by the agar dilution method were ≤1 μg/ml. With a clinical cefotaxime-resistant strain, Ah 2743, in an in vitro time-kill study, at an inoculum of 7 × 105 CFU/ml incubated with fluoroquinolones, cefotaxime, or minocycline at concentrations equal to twice the MICs, the inhibitory effect lasted for less than 6 h and regrowth occurred thereafter. In an animal model with female BALB/c mice intraperitoneally infected with an inoculum of 1.1 × 107 CFU of Ah 2743, more mice in the ciprofloxacin-treated group survived (72.2%) than in the cefotaxime-, minocycline-, or cefotaxime-minocycline-treated group (P < 0.00001, log rank test). However, there were similar fatality rates, ranging from 71.4 to 87.5%, among mice treated with any of five fluoroquinolones. With a larger inoculum, 4.9 × 107 CFU, mice in the ciprofloxacin-treated group survived longer than those in the minocycline-, cefotaxime-, or cefotaxime-minocycline-treated group (30 h versus 18, 12, and 12 h, respectively [P < 0.002, log rank test]). However, in mice infected with cefotaxime-susceptible Ah 2556, ciprofloxacin was as effective as cefotaxime-minocycline. Thus, our results suggest that ciprofloxacin is at least as effective as cefotaxime-minocycline against murine A. hydrophila infections, which warrants clinical studies to delineate its role in human infections.

More than 3,000 consecutive clinical bacterial isolates from 10 U.S. medical centers were subjected to standard broth microdilution and disk diffusion tests to determine their susceptibilities to levofloxacin, ofloxacin, D-ofloxacin, and ciprofloxacin. Levofloxacin was confirmed to be twice as active as ofloxacin and to have activity comparable to that of ciprofloxacin, with minor variations in activity against some species. The prevalence of resistant isolates was 7.1% to levofloxacin, 9.3% to ciprofloxacin, and 11.2% to ofloxacin. The susceptibilities of some species to the quinolones were less than those reported in previous studies. Pseudomonas aeruginosa isolates had the greatest variability in their susceptibilities to the three drugs between the participating centers. Two proposed zone size breakpoints for levofloxacin disk tests yielded similar low error rates. Ofloxacin and ciprofloxacin susceptibility test results correlated reasonably well with those of levofloxacin and could be used as surrogate indicators of levofloxacin susceptibility, but that resulted in some serious errors, and thus, direct testing of levofloxacin susceptibility is preferable. Replicate testing of standard quality control strains confirmed the established and proposed quality control parameters for all three quinolones tested.

To investigate emerging fluoroquinolone resistance in Neisseria gonorrhoeae isolated in Japan, we compared the in vitro antimicrobial susceptibilities of 79 gonococcal isolates from 1992 through 1993 to 14 fluoroquinolones and 14 other antibiotics with those of 27 isolates from between 1981 and 1984. The MICs at which 90% of the isolates were inhibited by nine fluroquinolones, including norfloxacin, enoxacin, ofloxacin, ciprofloxacin, tosufloxacin, lomefloxacin, fleroxacin, levofloxacin, and sparfloxacin, for isolates from 1992 to 1993 were 8- or 16-fold higher than those for isolates from 1981 to 1984. Furthermore, the MICs at which 90% of the isolates were inhibited by five fluroquinolones, including OPC-17116, T-3761, DU-6859a, AM-1155, and Q-35, that have recently been synthesized but have not yet been introduced for clinical use in Japan for isolates from 1992 to 1993 were also 2- to 16-fold higher than those for isolates from 1981 to 1984. The gonococcal isolates from 1992 to 1993 showed no significant decreases in susceptibility to beta-lactams, tetracyclines, macrolides, and spectinomycin, compared with those for isolates from 1981 to 1984. Our data indicate that the incidence of gonococcal strains with decreased susceptibilities to fluoroquinolones is increasing in Japan.

The in vitro activity of lomefloxacin (SC-47111; NY-198), a new difluorinated quinolone, was compared with those of ofloxacin, ciprofloxacin, fleroxacin, amoxicillin, cefuroxime, and trimethoprim against 585 recent clinical isolates and other strains with known mechanisms of resistance. The MICs of lomefloxacin against 90% of the members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and staphylococci were between 0.25 and 4 micrograms/ml. Ninety percent of Neisseria sp. and Haemophilus influenzae were susceptible to less than or equal to 0.06 micrograms/ml, and streptococci (including Streptococcus pyogenes, Streptococcus pneumoniae, and enterococci) and Bacteroides fragilis were susceptible to 8 micrograms/ml. Lomefloxacin was comparable in activity to fleroxacin and ofloxacin, but it was less active than ciprofloxacin. There was cross-resistance between the quinolone group of antimicrobial agents. The protein binding of lomefloxacin was 15.4%, and serum had little effect on the activity of the compound. However, urine at pH 5.0 decreased the activity by two- to eightfold compared with that at pH 7.0

The in vitro activity of the new fluoroquinolone HSR-903 was compared with those of ciprofloxacin, lomefloxacin, sparfloxacin, and levofloxacin. HSR-903 inhibited 90% of methicillin-susceptible and -resistant Staphylococcus aureus (MRSA) clinical isolates at 0.78 and 1.56 microg/ml, respectively, and its activity against MRSA was 16-fold higher than those of sparfloxacin and levofloxacin and 64-fold higher than that of ciprofloxacin. The MICs at which 90% of the isolates are inhibited (MIC90s) of HSR-903 for Streptococcus pyogenes and penicillin G-susceptible and -resistant Streptococcus pneumoniae (PRSP) were 0.10, 0.05, and 0.05 microg/ml, respectively. Against PRSP, the activity of HSR-903 was 4-fold higher than that of sparfloxacin and 32- to 256-fold higher than those of the other quinolones. The MIC90 of HSR-903 for Enterococcus faecalis was 0.20 microg/ml, and HSR-903 was more active than the other quinolones against enterococci. The activity of HSR-903 against members of the family Enterobacteriaceae and Pseudomonas aeruginosa was roughly similar to that of ciprofloxacin and greater than those of the other quinolones. Against Haemophilus influenzae, Moraxella catarrhalis, and Helicobacter pylori, HSR-903 was the most potent of the quinolones tested. The activity of HSR-903 was not affected by the medium, the inoculum size, or the addition of serum, but decreased under acidic conditions, as did those of the other quinolones tested. HSR-903 exhibited rapid bactericidal action and had a good postantibiotic effect on S. aureus and P. aeruginosa. HSR-903 inhibited supercoiling by DNA gyrase from Escherichia coli, but it was much less active against human topoisomerase II.

We compared the in vitro antibacterial activity of DV-7751a against gram-positive and -negative bacteria with those of quinolones currently available. MICs for 90% of the strains tested (MIC90s) against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis were 0.20, 0.39, 0.20, and 0.78 micrograms/ml, respectively. Moreover, MIC50s for DV-7751a against ofloxacin-resistant methicillin-resistant S. aureus were 4-, 8-, 16-, 32-, and 64-fold lower than those for tosufloxacin and sparfloxacin, levofloxacin, ofloxacin and fleroxacin, ciprofloxacin, and lomefloxacin, respectively. DV-7751a inhibited the growth of all strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Peptostreptococcus spp. at 0.39, 0.39, and 0.78 micrograms/ml, respectively, and was 4- to > 16-fold more active against enterococci at the MIC90 level than the other quinolones tested. The activity of DV-7751a against Pseudomonas aeruginosa was roughly comparable to those of levofloxacin and sparfloxacin at the MIC90 level and was two- to fourfold less than that of ciprofloxacin. DV-7751a showed activity comparable to those of levofloxacin and ciprofloxacin against the other glucose-nonfermenting bacteria Haemophilus influenzae, Neisseria gonorrhoeae, and Moraxella catarrhalis (MIC90s of 0.025, 0.20, and 0.10 micrograms/ml, respectively). DV-7751a activity was not affected by medium, inoculum size, or the addition of human serum but was decreased under acidic conditions and in human urine, as were the other quinolones tested. Time-kill curve studies demonstrated the rapid bactericidal action of DV-7751a against S. aureus, S. pneumoniae, Escherichia coli, and P. aeruginosa. The frequency of spontaneous resistance to DV-7751a was less than or equal to those of the reference drugs. DV-7751a inhibited the supercoiling activity of DNA gyrases from S. aureus, E. coli, and P. aeruginosa at concentrations comparable to those of levofloxacin and sparfloxacin.

Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.

A predictor panel of 300 clinical bacterial isolates (200 resistant to ciprofloxacin) was used to compare 5-micrograms disk diffusion test results with the MICs of ofloxacin (control), levofloxacin, and sparfloxacin. Regression analysis demonstrated high correlations between the methods for all three fluoroquinolones (r > or = 0.95). In order to minimize disk diffusion testing errors among the fluoroquinolone-resistant strains, the following modifications to previously proposed or published interpretive criteria were suggested: for levofloxacin, susceptible at > or = 17 mm (< or = 2 micrograms/ml) and resistant at < or = 13 mm (> or = 8 micrograms/ml); for sparfloxacin, susceptible at > or = 20 mm (< or = 1 microgram/ml) and resistant at < or = 16 mm (> or = 4 micrograms/ml). The study control drug, ofloxacin, did not appear to possess a significant error rate (5% minor error) when fluoroquinolone-resistant strains were tested, and no modifications were proposed. Under these proposed interpretive criteria, the absolute categorical agreements between standardized susceptibility testing methods for levofloxacin and sparfloxacin results were 91.3 and 94.0%, respectively (< or = 0.3% major errors and nil very major errors).

Objectives

The aim of this study was to assess the sensitivity, specificity and time to results of mycobacterial growth indicator tube (MGIT) 960, microscopic observation drug susceptibility (MODS) assay and nitrate reductase assay (NRA) compared with the gold standard agar proportion method (PM), and to determine whether there is cross-resistance between older-generation fluoroquinolones and moxifloxacin.

Methods

Mycobacterium tuberculosis isolates from culture-confirmed tuberculosis patients from 2002 to 2007 were tested for ofloxacin (2 mg/L) resistance by PM and MGIT 960. All isolates from 2005 and 2006 were also tested by MODS and NRA. Ofloxacin-resistant isolates by PM were further tested by all four methods using ciprofloxacin, levofloxacin and moxifloxacin. For each ofloxacin-resistant isolate, two ofloxacin-susceptible isolates were tested against all three fluoroquinolones using all four methods.

Results

Of the 797 M. tuberculosis isolates, 19 (2.4%) were ofloxacin-resistant by PM. MGIT 960 had 100% sensitivity (95% CI, 83%–100%) and specificity (95% CI, 99.5%–100%). Of the 797 isolates, 239 were from 2005 to 2006 and 6 of these (2.5%) were resistant by PM. MODS had 100% sensitivity (95% CI, 61%–100%) and specificity (95% CI, 98%–100%). NRA had 100% sensitivity (95% CI, 61%–100%) and 98.7% specificity (95% CI, 96%–99.6%). The median time to results was shorter using MGIT 960 (8 days), MODS (6 days) or NRA (9 days) compared with PM (21 days) (P < 0.001). All 19 ofloxacin-resistant isolates were resistant to ciprofloxacin, levofloxacin and moxifloxacin by PM.

Conclusions

MGIT 960, MODS and NRA are sensitive and specific and more rapid than PM for identifying fluoroquinolone resistance in M. tuberculosis. Ofloxacin resistance was associated with cross-resistance to ciprofloxacin, levofloxacin and moxifloxacin.

Fluoroquinolone (FLQ) drugs are a potent family of antibiotics used to treat infections including ocular infections. To determine if these antibiotics may be phototoxic to the eye, we exposed human lens epithelial cells to 0.125–1 mM FLQs [ciprofloxacin (Cipro), lomefloxacin (Lome), norfloxacin (Nor), and ofloxacin (Ofl)], the precursor quinolone nalidixic acid (Nalid), and UVA radiation (2.5 J/cm2). Based on fluorescence confocal microscopy, FLQs are diffused throughout the cytoplasm and preferentially located in the lysosomes of lens epithelial cells. Neither FLQ exposure alone nor UVA exposure alone reduced cell viability. However, with exposure to UVA radiation the FLQs studied (Cipro, Nor, Lome and Ofl) induced a phototoxic reaction that included necrosis, apoptosis, loss of cell viability as measured by MTS, and membrane damage as determined by the LDH assay. Both Nalid and all FLQs studied (Cipro, Nor, Lome and Ofl) photopolymerized the lens protein α-crystallin. Phototoxic damage to lens epithelial cells and/or α-crystallin will lead to a loss of transparency of the human lens. However, if precautions are taken to filter all UV radiation from the eye while taking these antibiotics, this eye damage may be prevented.

Levofloxacin is the L isomer of ofloxacin, a racemic mixture in which the L stereochemical form carries the antimicrobial activity. Levofloxacin is more active than former quinolones against gram-positive bacteria, making it potentially useful against such pathogens. In this study, levofloxacin was compared to ciprofloxacin, flucloxacillin, and vancomycin for the treatment of experimental endocarditis due to two methicillin-susceptible Staphylococcus aureus (MSSA) and two methicillin-resistant S. aureus (MRSA) isolates. The four test organisms were susceptible to ciprofloxacin, the levofloxacin MICs for the organisms were low (0.12 to 0.25 mg/liter), and the organisms were killed in vitro by drug concentrations simulating both the peak and trough levels achieved in human serum (5 and 0.5 mg/liter, respectively) during levofloxacin therapy. Rats with aortic endocarditis were treated for 3 days. Antibiotics were injected with a programmable pump to simulate the kinetics of either levofloxacin (350 mg orally once a day), ciprofloxacin (750 mg orally twice a day), flucloxacillin (2 g intravenously four times a day), or vancomycin (1 g intravenously twice a day). Levofloxacin tended to be superior to ciprofloxacin in therapeutic experiments (P = 0.08). More importantly, levofloxacin did not select for resistance in the animals, in contrast to ciprofloxacin. The lower propensity of levofloxacin than ciprofloxacin to select for quinolone resistance was also clearly demonstrated in vitro. Finally, the effectiveness of this simulation of oral levofloxacin therapy was at least equivalent to that of standard treatment for MSSA or MRSA endocarditis with either flucloxacillin or vancomycin. This is noteworthy, because oral antibiotics are not expected to succeed in the treatment of severe staphylococcal infections. These good results obtained with animals suggest that levofloxacin might deserve consideration for further study in the treatment of infections due to ciprofloxacin-susceptible staphylococci in humans.

In vitro activity of LB20304 against 1,231 clinical isolates was evaluated and compared with those of ciprofloxacin, sparfloxacin, lomefloxacin, and ofloxacin. LB20304 demonstrated the most potent activity against gram-positive bacteria. It was 32- to 64-fold more active than ciprofloxacin against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-resistant Staphylococcus epidermidis, and Streptococcus pneumoniae (penicillin G resistant). LB20304 was also highly active against most members of the family Enterobacteriaceae. Its activity was more potent than those of sparfloxacin, ofloxacin, and lomefloxacin and comparable to that of ciprofloxacin. The protective activities of LB20304 against systemic infections caused by gram-positive bacteria in mice were superior to those of ciprofloxacin and sparfloxacin. Against infections by gram-negative bacteria, LB20304 was slightly less active than ciprofloxacin.

A-80556 is a novel fluoroquinolone with potent antibacterial activity against gram-positive, gram-negative, and anaerobic organisms. A-80556 was more active than ciprofloxacin, ofloxacin, lomefloxacin, and sparfloxacin against gram-positive bacteria. A-80556 was particularly active against Staphylococcus aureus (MIC for 90% of isolates [MIC90], 0.12 microgram/ml, relative to fluoroquinolone-susceptible strains) and Streptococcus pneumoniae (MIC90, 0.12 microgram/ml). A-80556 was also the most active of the quinolones tested against ciprofloxacin-resistant S. aureus, with an MIC90 of 4.0 micrograms/ml; that of ciprofloxacin was > 128 micrograms/ml. However, the significance of this activity is not known. A-80556 was slightly less active against Escherichia coli (MIC90, 0.06 microgram/ml) and other enteric organisms than ciprofloxacin (MIC90 for E. coli, < or = 0.03 microgram/ml). A-80556 was slightly less active against Pseudomonas aeruginosa (MIC90, 4.0 micrograms/ml) than ciprofloxacin (MIC90, 2.0 micrograms/ml) and more active against Acinetobacter spp. (respective MIC90s, 0.12 and 0.5 microgram/ml). A-80556 was also the most active compound against anaerobes. Against Bacteroides fragilis, the MIC90 of A-80556 was 2.0 micrograms/ml; that of ciprofloxacin was 16 micrograms/ml. The in vivo efficacy of A-80556 in experimental models with both gram-positive and gram-negative infections was consistent with the in vitro activity and pharmacokinetics and oral absorption in mice.

The pharmacodynamic properties of levofloxacin (an optically active isomer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combination with rifampin, were evaluated over 24 to 48 h against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) in an in vitro infection model. The incidence of the emergence of resistance among the test strains was also determined. The fluoroquinolones were administered to simulate dosage regimens of 200 mg, 400 mg given intravenously (i.v.) every 12 h (q12h), and 400 and 800 mg given i.v. q24h. Rifampin was dosed at 600 mg i.v. q24h. Although the MICs and MBCs of the quinolones were similar (< or = 0.49 microgram/ml), levofloxacin was the most potent agent in time-kill studies on the basis of the time required to achieve a 99.9% reduction in the number of log10 CFU per milliliter (e.g., with the regimen of levofloxacin [400 mg q24h, 6.5 h] versus ofloxacin [12.5 h], P < 0.024, and levofloxacin versus ciprofloxacin [6.5 versus 9.0 h], P < 0.0017) against MSSA 1199. The killing activity of levofloxacin was similar to that of ofloxacin against MRSA 494 (time to achieve a 99.9% reduction in the number of log10 CFU per milliliter, 11.1 versus 13.8 h, respectively). Levofloxacin and ofloxacin dosed once daily demonstrated greater bactericidal activity than when they were dosed twice daily against MSSA 1199. Resistance to levofloxacin or ofloxacin was not observed with any dosage regimen. Furthermore, resistance to ofloxacin was not detected when the half-life was reduced from 6 to 3 h. Regrowth and stable resistance (65-fold increase in the MIC for MSSA 1199; 16-fold increase in the MIC for MRSA 494) were noted within 24 h of exposure to ciprofloxacin at 200 mg q12h. Combination therapy with rifampin prevented the emergence of resistance to ciprofloxacin. Neither DNA gyrase alteration nor an energy-dependent efflux process mediated by the norA gene appeared to be responsible for the resistance observed. Our data suggest that with levofloxacin there is a more rapid onset of bactericidal activity than with ofloxacin or ciprofloxacin against MSSA 1199 and that the activity of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even when the pharmacokinetics of the drug were set to equal those of ciprofloxacin, suggesting that ofloxacin differs from ciprofloxacin irrespective of time of exposure. The resistance to ciprofloxacin that developed in our vitro model may be mediated by the cfx-ofx locus, which has been shown to be associated with low-level fluoroquinolone resistance. Overall, levofloxacin demonstrated potent bactericidal activity against S. aureus, without the emergence of resistance in our infection model. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not synergistic but prevented the emergence of ciprofloxacin resistance.

Images

A national survey on susceptibility patterns of 334 Pseudomonas aeruginosa isolates from intensive care units and hematology and oncology wards from 13 Italian hospitals compared the in vitro activity of levofloxacin, an injectable oral fluoroquinolone, to those of ciprofloxacin, ofloxacin, ceftazidime, imipenem, amikacin, and gentamicin. Amikacin and imipenem had the best susceptibility profiles. The activity of levofloxacin was superior to those of the other quinolones and was comparable to that of ceftazidime. The effect of levofloxacin in vitro on P. aeruginosa clinical isolates suggests that further clinical investigations are warranted.

CFC-222 is a novel fluoroquinolone containing a C-7 bicyclic amine moiety with potent antibacterial activities against gram-positive, gram-negative, and anaerobic organisms. We compared the in vitro and in vivo activities of CFC-222 with those of ciprofloxacin, ofloxacin, and lomefloxacin. CFC-222 was more active than the other fluoroquinolones tested against gram-positive bacteria. CFC-222 was particularly active against Streptococcus pneumoniae (MIC at which 90% of isolates are inhibited [MIC90], 0.2 microg/ml), Staphylococcus aureus (MIC90, 0.2 microg/ml for ciprofloxacin-susceptible strains), and Enterococcus faecalis (MIC90, 0.39 microg/ml). Against Escherichia coli and other members of the family Enterobacteriaceae, CFC-222 was slightly less active than ciprofloxacin (MIC90s for E. coli, 0.1 and 0.025 microg/ml, respectively). The in vitro activity of CFC-222 was not influenced by inoculum size, medium composition, or the presence of horse serum. However, its activity was decreased significantly by a change in the pH of the medium from 7.0 to 6.0, as was the case for the other quinolones tested. The in vivo protective efficacy of CFC-222 by oral administration was greater than those of the other quinolones tested in a mouse model of intraperitoneally inoculated systemic infection caused by S. aureus. CFC-222 exhibited efficacy comparable to that of ciprofloxacin in the same model of infection caused by gram-negative organisms, such as E. coli and Klebsiella pneumoniae. In this infection model, CFC-222 was slightly less active than ciprofloxacin against Pseudomonas aeruginosa. These results suggest that CFC-222 may be a promising therapeutic agent in various bacterial infections.

A test battery of bacterial strains with a high incidence of resistance to fluoroquinolones was studied to determine the extent to which susceptibility to levofloxacin could be predicted from susceptibility tests performed with ciprofloxacin or ofloxacin as reagents. Isolates susceptible or intermediately susceptible to ofloxacin (MICs < or = 4 micrograms/ml) may be regarded as susceptible to levofloxacin, with the exception of Enterococcus faecium. Ciprofloxacin-susceptible isolates (MICs < or = 1 micrograms/ml) were also completely susceptible to levofloxacin. Clinical laboratories could use either of the currently used fluoroquinolones (ciprofloxacin or ofloxacin) to predict levofloxacin activity and spectrum with little risk of false-susceptible errors (0.0 to 1.3%). Results obtained with ofloxacin are superior in maximizing recognition of levofloxacin-susceptible clinical isolates.

The present National Committee for Clinical Laboratory Standards (NCCLS) guideline for testing Neisseria gonorrhoeae quinolone susceptibility defines only a susceptible category for ciprofloxacin, enoxacin, lomefloxacin, and ofloxacin, while susceptible, intermediate, and resistant categories are defined for fleroxacin. To further define the criteria for detection of quinolone resistance in gonococci, by standard disk diffusion and agar dilution methodologies recommended by the NCCLS, we tested 29 strains of quinolone-resistant N. gonorrhoeae (QRNG) recently isolated from ofloxacin-treated patients who were considered clinical failures. Regression analyses were performed on these results together with those of another 20 strains showing reduced susceptibility and 13 fully susceptible strains (ofloxacin MICs of < or = 0.25 microgram/ml). With 5-micrograms ofloxacin disks, resistance in 27 (93.1%) of the QRNG strains (MICs of > 1 microgram/ml) was detected by the criterion of a zone diameter of < 22 mm, while in the remaining 2 (6.9%), the disks failed to detect resistance. A cluster of 15 highly resistant strains showed ofloxacin MICs of > 4 micrograms/ml and zone diameters of < 13 mm. When tested with 5-micrograms ciprofloxacin disks, the corresponding values for resistance and high-level resistance of these QRNG strains were < 25 mm (MICs of > 0.5 micrograms/ml) and < 15 mm (MICs of > 2 micrograms /ml), respectively. Six strains for which ofloxacin MICs were > or = 8 micrograms/ml showed no zones at all with both 5-micrograms ofloxacin and 5-micrograms ciprofloxacin disks. These QRNG strains are now firmly established in the Southeast Asia region, and it is important for clinical laboratories to recognize these clinically resistant strains and to monitor their spread.

Abstract

Purpose

Multidrug resistance (MDR) represents a major obstacle to the success of antimicrobial fluoroquinolone (FQ) therapy. MDR-associated efflux protein pumps antimicrobial agents out of the corneal cells, leading to suboptimal eradication of microbes. This article examines whether long-term FQ (levofloxacin, ofloxacin, and gatifloxacin) therapy can modify the MDR phenotype (P-glycoprotein [P-gp]) on corneal epithelial cells (Statens Seruminstitut Rabbit Cornea [SIRC]).

Methods

To study the effect of FQ, SIRC cells without any exposure to FQ (control) were compared with the cells exposed to ofloxacin, levofloxacin, and gatifloxacin at a concentration of 10 μg/mL for 3 weeks. Efflux activity of P-gp was assessed by in vitro uptake studies (fluorescent and radioactive), flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR).

Results

In the presence of FQ, elevated P-gp expression was noted with uptake, flow cytometry, and qRT-PCR analyses. This study confirms that long-term exposure to antibiotics, particularly FQ, can induce overexpression of P-gp efflux transporter present on the corneal cells. P-gp overexpression is commonly noticed in anticancer drug resistance cell lines; however, for the first time, this report describes overexpression of P-gp due to FQ exposure.

Conclusions

Based on this result, it is suggested that strategies should be developed and implemented not only to overcome resistance to ocular pathogen but also to FQ-induced cellular resistance.

The in vitro activity of OPC-17116, a new C-5 methyl fluoroquinolone, was compared with the activities of other fluoroquinolones. OPC-17116 inhibited 50% of the members of the family Enterobacteriaceae tested and 90% of Haemophilus influenzae, Neisseria species, and Moraxella catarrhalis isolates at less than or equal to 0.25 microgram/ml. At less than or equal to 2 micrograms/ml, 90% of the Enterobacteriaceae were inhibited, which was comparable to or better than the activities of fleroxacin, ofloxacin, and lomefloxacin but less than the activity of ciprofloxacin. OPC-17116 inhibited 90% of the staphylococci tested at less than or equal to 0.25 micrograms/ml, but it did not inhibit methicillin-resistant, ciprofloxacin-resistant Staphylococcus aureus or Staphylococcus epidermidis. Group A, B, C, F, and G streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.5 microgram/ml, being four-fold more active than ciprofloxacin and ofloxacin. Tosufloxacin was the most active agent tested against gram-positive cocci. OPC-17116 inhibited Bacteroides fragilis at 4 micrograms/ml. There was a minimal effect of inoculum size on MIC, and the MBCs were within 1 dilution of the MICs. The activity of OPC-17116 was decreased at pH 6 and in the presence of high Mg2+ concentrations, but it was unaffected by human serum. OPC-17116 showed a postantibiotic effect against Pseudomonas aeruginosa and Staphylococcus aureus similar to the postantibiotic effects reported for other fluoroquinolones. The frequency of spontaneous single-step resistance was low (less than 10(-9)), but repeated passage of organisms in the presence of OPC-17116 resulted in the selection of resistant isolates.

The in vitro spectrum of a novel des-fluoro(6) quinolone, BMS-284756, was compared with those of five fluoroquinolones (trovafloxacin, moxifloxacin, levofloxacin, ofloxacin, and ciprofloxacin). BMS-284756 was among the most active and often was the most active quinolone against staphylococci (including methicillin-resistant strains), streptococci, pneumococci (including ciprofloxacin-nonsusceptible and penicillin-resistant strains), and Enterococcus faecalis. BMS-284756 inhibited ≈60 to ≈70% of the Enterococcus faecium (including vancomycin-resistant) strains and 90 to 100% of the Enterobacteriaceae strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint (≤4 μg/ml). Against the nonfermenters, BMS-284756 inhibited 90 to 100% of Pseudomonas fluorescens, Pseudomonas stutzeri, Stenotrophomonas maltophilia, Flavobacterium spp., and Acinetobacter spp. and 72% of Pseudomonas aeruginosa strains at 4 μg/ml. Against anaerobic bacteria, BMS-284756 was among the most active, inhibiting essentially all strains tested. It had very low MICs against the fastidious and atypical microbial species, in particular against mycoplasmas or ureaplasmas, Borrelia burgdorferi, chlamydia, and gonococci. These results indicate that with its broad antibacterial spectrum, BMS-284756 should be evaluated clinically for the treatment of community and nosocomial infections.

The in vitro activity of sparfloxacin, a new difluorinated quinolone, was evaluated against 857 gram-positive and gram-negative clinical isolates and compared with those of ciprofloxacin, norfloxacin, ofloxacin, fleroxacin, and lomefloxacin. The MIC of sparfloxacin for 90% of the members of the family Enterobacteriaceae tested was 0.5 microgram/ml (range, 0.06 to 4.0 micrograms/ml); only for members of the genera Serratia, Citrobacter, and Providencia were MICs above 1 microgram/ml. Some 90% of Pseudomonas aeruginosa isolates were inhibited by 8 micrograms of the drug per ml. The MICs for 90% of Staphylococcus spp. and Enterococcus faecalis were 0.12 and 2 micrograms/ml, respectively. All (100%) Streptococcus pneumoniae strains were inhibited by 0.5 microgram/ml. The inoculum size had little effect on either the MIC or the MBC of sparfloxacin. An increase in the magnesium concentration from 1.1 to 8.4 mM increased the MIC between 2 and 10 times, depending on the genus tested. Sparfloxacin was less active at pH 5. The antibacterial activity of sparfloxacin against gram-positive bacteria was generally higher than those of the quinolones with which it was compared; against Streptococcus pneumoniae, sparfloxacin was four- and eightfold more active than ofloxacin and ciprofloxacin, respectively. The activity of sparfloxacin against gram-negative rods was generally comparable to that of ciprofloxacin except against Enterobacter and Acinetobacter spp., Pseudomonas cepacia, Xanthomonas maltophilia, and Alcaligenes and Flavobacterium spp., against which sparfloxacin was the most active quinolone.