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PubMed1998

Cross-reactivity in murine fluoroquinolone photoallergy: exclusive usage of TCR Vbeta13 by immune T cells that recognize fluoroquinolone-photomodified cells.

Fluoroquinolone antibacterial agents are well known to elicit photosensitivity as an adverse effect, and their cross-reactivity has been clinically documented. The photoallergenicity of fluoroquinolones is mainly derived from their photohaptenic moiety, and photomodification of skin epidermal cells with fluoroquinolones is thought to be an initial step for this photoallergy. Here we have explored, both in vivo and in vitro, T cell responses to fluoroquinolone-photomodified cells, focusing on their photoantigenic cross-reactivity. Cells were derivatized with fluoroquinolones under exposure to UV-A, and fluoroquinolone photoadducts were detected in photomodified cells by immunostaining, flow cytometry, and cell ELISA using fluoroquinolone-specific mAb. T cell-mediated hypersensitivity induced and elicited by s.c. injection of fluoroquinolone-photomodified epidermal cells was cross-reactive among six fluoroquinolones. In addition, lymph node cells from mice sensitized with fluoroquinolone-photomodified cells proliferated well in vitro not only to Langerhans cell-enriched epidermal cells photoderivatized with corresponding fluoroquinolone, but also to those photomodified with any of five other fluoroquinolones, supporting their cross-reactivity. In three fluoroquinolones tested, Th1 populations that expanded after in vitro photoantigenic stimulation of immune lymph node cells expressed the same Vbeta13 of TCR. The sensitivity could be transferred by the i.v. administration of this Vbeta13+ T cell line into naive recipients, in which a high percentage of Vbeta13+ cells infiltrated at the challenge site. These findings suggest that these fluoroquinolones carry the same photoantigenic epitope, which is recognized by Vbeta13+ T cells, leading to fluoroquinolone photosensitivity and cross-reactivity.

Adoptive Transfer↗

PubMed2005

Fluoroquinolone resistance of Escherichia coli at a cancer center: epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia.

The aim of the present study was to investigate the epidemiologic evolution of fluoroquinolone resistance of E. coli clinical isolates from patients admitted to a hematology-oncology service where fluoroquinolone prophylaxis during neutropenia was recommended as the standard of care for many years but was then discontinued in a trial conducted in patients with acute leukemia. Fluoroquinolones had been shown to decrease the incidence of gram-negative bacteremia in cancer patients with neutropenia, yet it was thought that the emergence of resistance in Escherichia coli and other gram-negative bacteria may have caused a progressive lack of efficacy of fluoroquinolone prophylaxis. Epidemiologic surveillance of fluoroquinolone resistance of E. coli clinical isolates at our cancer center since 1992 showed a continuing influx of new clones not previously observed in the population of cancer patients, an increase in the number of cancer patients per year colonized and/or infected by fluoroquinolone-resistant E. coli (1992-1994, 10-16 patients; 1995-1997, 24-27 patients), and a resistance rate of >50% among E. coli bloodstream isolates of hematology-oncology patients. A 6-month fluoroquinolone prophylaxis discontinuation intervention trial in 1998 suggested that despite increasing resistance among E. coli isolates, fluoroquinolone prophylaxis in acute leukemia patients was still effective in the prevention of gram-negative bacteremia (incidence rates, 8% during the pre-intervention period vs. 20% after discontinuation; p<0.01). The resumption of fluoroquinolone prophylaxis in acute leukemia patients thereafter decreased the incidence of gram-negative bacteremia to the pre-intervention level (9%; p=0.03), while the proportion of in vitro fluoroquinolone resistance in E. coli bacteremia isolates again increased (from 15% during the intervention period to >50% in the post-intervention period). Relative rates of resistance thus were a poor indicator of the potential clinical benefits associated with fluoroquinolone prophylaxis in cancer patients.

Adolescent↗

PubMed2001

In vivo selection of Pseudomonas Aeruginosa with decreased susceptibilities to fluoroquinolones during fluoroquinolone treatment of urinary tract infection.

OBJECTIVES: To present a case of fluoroquinolone treatment failure in urinary tract infection caused by Pseudomonas aeruginosa, accompanied by in vivo selection of the post-treatment isolate that showed decreased susceptibilities to fluoroquinolones, and to report fluoroquinolone resistance mechanisms in the post-treatment isolate. METHODS: A patient with urinary tract infection was treated with a suboptimal dose of a fluorinated quinolone, gatifloxacin. P. aeruginosa strains were isolated before and after fluoroquinolone treatment. The pretreatment and post-treatment isolates were examined for relatedness by arbitrarily primed polymerase chain reaction. For these isolates, the minimum inhibitory concentration of antimicrobial agents was determined and mutations in the target genes (gyrA and parC) and regulatory genes (mexR and nfxB) for drug efflux pumps were analyzed. RESULTS: Failure of fluoroquinolone treatment of urinary tract infection was observed. The post-treatment isolate, which was assumed to be isogenic to the pretreatment isolate, exhibited fourfold to 16-fold increases in the MIC of fluoroquinolones. In this isolate, a new mutation, not observed in the pretreatment isolate, was found only in the gyrA gene, resulting in an amino acid change of aspartic acid to asparagine in codon 87 of GyrA. CONCLUSIONS: The P. aeruginosa isolate that was initially susceptible to fluoroquinolones showed decreased susceptibility to fluoroquinolones after treatment with a suboptimal dose of one fluoroquinolone. In the post-treatment isolate, the alteration of GyrA would be responsible for the decreased susceptibility to fluoroquinolones. We should be aware that inappropriate use of fluoroquinolones could select such a strain harboring a quinolone resistance-associated alteration of DNA gyrase.

Aged↗

PubMed2006

Fluoroquinolone-associated anaphylaxis in spontaneous adverse drug reaction reports in Germany: differences in reporting rates between individual fluoroquinolones and occurrence after first-ever use.

BACKGROUND: The frequency of fluoroquinolone-associated anaphylaxis has been estimated to be 1.8-23 per 10 million days of treatment based on spontaneous reports. It is unknown whether there are differences between the reporting rates of anaphylaxis with individual fluoroquinolones. According to pathophysiology, anaphylaxis may be immune mediated (anaphylactic) or not (anaphylactoid). The latter may occur after first-ever intake since no sensitisation phase is necessary. OBJECTIVE: To analyse spontaneous reports of fluoroquinolone-associated anaphylaxis contained in the spontaneous adverse drug reaction database of the Federal Institute for Drugs and Medical Devices in Germany with regard to differences in reporting rates between various fluoroquinolones, the previous intake and the time to onset of the reaction. METHODS: All fluoroquinolone-associated cases of anaphylaxis, anaphylactic shock, and anaphylactic/anaphylactoid reaction spontaneously reported to the Federal Institute for Drugs and Medical Devices between 1 January 1993 and 31 December 2004 were identified and assessed with regard to the correctness of the diagnosis of anaphylaxis, the causal relationship with the drug, the previous intake of fluoroquinolones and the time to onset of the reaction. RESULTS: In 166 of 204 cases identified, the diagnosis of anaphylaxis and a causal relationship with the drug were considered at least possible. Moxifloxacin, levofloxacin, ciprofloxacin and ofloxacin accounted for 90 (54%), 25 (15%), 21 (13%) and 16 (10%) of the 166 cases, respectively. The corresponding reporting rates per 1 million defined daily doses based on crude estimates of exposure were 3.3, 0.6, 0.2 and 0.2 for moxifloxacin, levofloxacin, ciprofloxacin and ofloxacin, respectively. The occurrence of anaphylaxis after the first dose or within the first three days was reported in 71 of 166 (43%) cases, but no information on prior exposure with this or any other fluoroquinolone was provided with these reports. In 21 of 166 (13%) cases, the reaction occurred within the first 3 days and it was stated that the particular fluoroquinolone had never been taken before. CONCLUSIONS: Anaphylaxis appears to be associated with the fluoroquinolone class of antibacterials. Observed differences in reporting rates should be further investigated. Fluoroquinolone-associated anaphylaxis may occur after first-ever intake of the agent.

Adult↗

PubMed2004

Predicting hospital rates of fluoroquinolone-resistant Pseudomonas aeruginosa from fluoroquinolone use in US hospitals and their surrounding communities.

Rates of fluoroquinolone resistance among Pseudomonas aeruginosa in hospitals are increasing, but interhospital variability is great. We sought to determine whether this variability correlated to fluoroquinolone use in hospitals and in the surrounding community. Hospital quinolone use in 1999 (24 hospitals) through 2001 (35 hospitals) was determined from billing records. The number of fluoroquinolone prescriptions within a 10-mile (approximately 16-km) radius of each hospital was determined for 1999 and 2000. Hospital fluoroquinolone use increased from 1999 through 2001, from 137 to 163 defined daily doses (DDD)/1000 patient-days (P=.01). The rate of community fluoroquinolone use also increased, from 2.3 to 2.8 DDD/1000 inhabitant-days (P<.001). Rates of fluoroquinolone-resistant P. aeruginosa increased from 29% in 1999 to 36% in 2001 (P=.003). Both community and hospital fluoroquinolone use were predictive of rates of fluoroquinolone-resistant P. aeruginosa. Levofloxacin was associated with resistance, but ciprofloxacin was not. Most of the variability in resistance rates is explained by volume of fluoroquinolone use, both in the hospital and the surrounding community.

Adolescent↗

PubMed2003

Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions.

OBJECTIVE: To analyse and compare with one another and with other antibacterial drugs the adverse drug reactions (ADRs) of the different fluoroquinolones currently used in Italy, spontaneously reported from doctors in three northern Italian regions. METHODS: The data on fluoroquinolones and other antibacterials were obtained from the spontaneous reporting system database of Emilia Romagna, Lombardy and the Veneto, which are the principal contributors to the Italian spontaneous surveillance system. The fluoroquinolone ADRs with a causality assessment of certain, probable or possible (according to WHO criteria), reported between January 1999 and December 2001, were selected and toxicity profiles of individual drugs were described and compared with one another. The reports were also correlated with sex and age of patients and with regional prescription data to estimate individual fluoroquinolone reporting rate of adverse events. RESULTS: During the study period, 10 011 reports were received by the system (a mean annual reporting rate of approximately 185 per million inhabitants): 1920 referred to systemic antimicrobials, of which 432 (22.5%) involved fluoroquinolones. Pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin (221) and lomefloxacin (196). The most frequently reported reactions to fluoroquinolones involved the skin, but their percentage (25%) was significantly lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas the percentages of reactions involving the central nervous (12.2 vs 3.6%), musculoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were significantly higher (p < 0.01). We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05). Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin. CONCLUSIONS: The differences in the safety profiles should be taken into account when prescribing a fluoroquinolone to individual patients.

Adolescent↗

PubMed1997

Fluoroquinolone treatment failure in gonorrhea. Emergence of a Neisseria gonorrhoeae strain with enhanced resistance to fluoroquinolones.

BACKGROUND AND OBJECTIVES: Although emergence of clinical isolates of Neisseria gonorrhoeae with decreased susceptibilities to fluoroquinolones and treatment failures in gonorrhea have been reported, there have been no clinical reports that fluoroquinolone treatments actually select quinolone-resistant strains, nor have isolates that exhibited clinically significant resistance been analyzed for resistance mechanisms. GOALS: To report a case of fluoroquinolone treatment failure in gonorrhea and emergence of a posttreatment isolate with enhanced resistance to fluoroquinolones; and to study mechanisms of quinolone resistance in the isolates from this patient. STUDY DESIGN: A patient with gonococcal urethritis treated with ofloxacin, 200 mg, three times daily for 5 days is described. Pretreatment and posttreatment isolates were tested for minimum inhibitory concentrations (MICs) of antimicrobial agents and analyzed for alterations in DNA gyrase and topoisomerase IV. They were also examined for ofloxacin uptake. RESULTS: Treatment failure with multiple doses of ofloxacin was observed in this case of gonorrhea. The pretreatment isolate showed decreased susceptibilities to fluoroquinolones (MIC of ofloxacin, 1.0 mg/l; MIC of ciprofloxacin, 0.25 mg/l), and had amino acid changes of Ser-91-->Phe in GyrA and Ser-87-->Ile in ParC. The posttreatment isolate exhibited an increase in resistance to fluoroquinolones (MIC of ofloxacin, 8.0 mg/l; MIC of ciprofloxacin, 1.0 mg/l). This isolate had identical alterations in GyrA and ParC, but exhibited significantly reduced uptake of ofloxacin. This isolate also showed a small decrease in susceptibilities to cephalosporins. CONCLUSIONS: Alterations in DNA gyrase and topoisomerase IV confer clinically significant resistance to fluoroquinolones in N. gonorrhoeae strains. Treatment with multiple doses of fluoroquinolones is likely to bring about selection of more fluoroquinolone-resistant strains of N. gonorrhoeae and to influence susceptibilities to cephalosporins.

Adult↗

PubMed1994

Fluoroquinolone use and fluoroquinolone resistance: is there an association?

In an assessment of potential risk factors for nosocomial infections caused by fluoroquinolone-resistant gram-negative organisms, 68 patients who developed a nosocomial infection caused by a fluoroquinolone-resistant gram-negative bacillus were compared with 191 patients who developed a nosocomial infection caused by a fluoroquinolone-susceptible gram-negative bacillus. A history of previous infection, immunosuppression, prior receipt of fluoroquinolones, and hospitalization on the burn unit were independent risk factors. Except for immunosuppression, the same risk factors were identified when the 50 patients whose isolates were resistant to fluoroquinolones, aminoglycosides, and beta-lactam antibiotics were compared with the 95 patients whose isolates were susceptible to all of these classes of antimicrobial agents. The identification of hospitalization on the burn unit as a risk factor was attributable to an outbreak of infections caused by a resistant strain of Pseudomonas aeruginosa during the study period. The occurrence of nosocomial outbreaks and the selective pressure of fluoroquinolone use were the main exogenous risk factors involved in the emergence of resistance to fluoroquinolones.

Adolescent↗

PubMed2006

Characterization of fluoroquinolone-resistant beta-hemolytic Streptococcus spp. isolated in North America and Europe including the first report of fluoroquinolone-resistant Streptococcus dysgalactiae subspecies equisimilis: report from the SENTRY Antimicrobial Surveillance Program (1997-2004).

Beta-hemolytic streptococci are common bacterial pathogens that can cause serious invasive disease, and although this group of species has remained susceptible to the fluoroquinolone class, resistant strains have been reported. This multicenter investigation determined the rate of fluoroquinolone-resistant beta-hemolytic streptococci using the SENTRY Antimicrobial Surveillance Program network data (1997-2004). Forty-seven surveillance culture isolates of beta-hemolytic streptococci from North America and Europe with elevated levofloxacin MIC results (2 to >32) microg/mL were tested for susceptibility to other fluoroquinolones including ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, and moxifloxacin using reference broth microdilution and Etest (BIODISK, Solna, Sweden) methods. Strains were characterized using polymerase chain reaction and sequencing to detect mutations in the quinolone-resistance determining region (QRDR). The beta-hemolytic streptococci isolates with reduced fluoroquinolone susceptibility included the following Lancefield groups: A (Streptococcus pyogenes; 9 strains), B (Streptococcus agalactiae; 24 strains), C and G (14 strains). Vitek and API 20 strep (bioMerieux, Hazelwood, MO) identification systems, as well as conventional biochemical methods and colony morphology, were used to confirm the organism identifications. The overall potency (MIC90 in microg/mL) for the fluoroquinolones against all tested beta-hemolytic streptococci showed the following rank order: gemifloxacin (0.06) > garenoxacin (0.12) > moxifloxacin (0.25) > gatifloxacin (0.5) > levofloxacin = ciprofloxacin (1). The rate of levofloxacin-resistant beta-hemolytic streptococci in the SENTRY program was 0.14% (Europe) and 0.51% (North America) during the study period. All levofloxacin-resistant strains tested by molecular methods had significant mutations in either parC (position 79 or 83) and/or gyrA (position 81 or 85). All but 2 isolates with high-level resistance to levofloxacin (>32 microg/mL) had gyrA mutations. Strains with lower MIC values to levofloxacin (2-4 microg/mL) only had mutations in parC. The increasing rate of fluoroquinolone-resistant streptococci including Streptococcus pneumoniae, viridans group streptococci, and the more recently reported beta-hemolytic streptococci, is becoming a clinical concern due to the morbidity and mortality caused by these pathogens.

Adolescent↗

PubMed2000

Antimicrobial activity of gemifloxacin (SB-265805), a newer fluoroquinolone, against clinical isolates of Neisseria gonorrhoeae, including fluoroquinolone-resistant isolates.

Antimicrobial activity of gemifloxacin (SB-265805), a newly developed fluoroquinolone, to Japanese isolates of Neisseria gonorrhoeae was compared with those of various fluoroquinolones, including norfloxacin, ciprofloxacin, tosufloxacin, levofloxacin, sparfloxacin, and trovafloxacin. Among the fluoroquinolones tested, gemifloxacin was most active against N. gonorrhoeae isolates. The MIC90 values of gemifloxacin for 94 N. gonorrhoeae isolated from 1992 through 1993 and 100 isolated from 1996 through 1997 were 0.03 and 0.125 microg/ml, respectively. On the other hand, MIC90 values of the other fluoroquinolone for the 1992-1993 isolates and the 1996-1997 isolates ranged from 0.125 to 2 microg/ml and from 0.5 to 8 microg/ml, respectively. Gemifloxacin was also the most potent fluoroquinolone against 31 ciprofloxacin-resistant isolates with the ciprofloxacin MIC of 1 to 16 microg/ml, for which the gemifloxacin MIC50 and MIC90 values were 0.25 and 2 microg/ml, respectively. Moreover, the activity of gemifloxacin against fluoroquinolone-resistant gonococcal isolates containing multiple amino acid substitutions in both GyrA and ParC proteins was superior to those of the other compounds.

Amoxicillin↗

PubMed1997

Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds.

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.

4-Quinolones↗

PubMed2003

Relationship between fluoroquinolone use and changes in susceptibility to fluoroquinolones of selected pathogens in 10 United States teaching hospitals, 1991-2000.

We retrospectively examined the relationship between fluoroquinolone use and the susceptibilities of 11 bacterial pathogens to fluoroquinolones in 10 US teaching hospitals from 1991 through 2000. Statistical significance was determined by 2-way analysis of variance, with the number of isolates tested each year as a weighting factor. The analysis of baseline-to-end point change in the percentage of susceptibility and the slope of the regression line (trend line) for logit percentage of susceptibility showed that the overall percentage of susceptibility to fluoroquinolones decreased significantly during the study period (P<.05) and that change in percentage of susceptibility was significantly related to change in fluoroquinolone use (P<.05). Particularly notable were the decreases in the susceptibilities of Pseudomonas aeruginosa, Proteus mirabilis, and Escherichia coli (decreases of 25.1%, 11.9%, and 6.8%, respectively).

Anti-Infective Agents↗

PubMed2002

Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance.

In this study the in vitro activities and pharmacodynamic properties of moxifloxacin, levofloxacin, gatifloxacin and gemifloxacin were compared on recently isolated respiratory pathogens and strains of Streptococcus pneumoniae with known mechanisms of fluoroquinolone resistance. In addition, the resistance selection frequencies of moxifloxacin and levofloxacin on three recently isolated respiratory pathogens and four strains of S. pneumoniae with known mechanisms of fluoroquinolone resistance were investigated. The four fluoroquinolones had similar activities against both Moraxella catarrhalis (MIC(90)s 0.015-0.06 mg/L) and Haemophilus influenzae (MIC(90)s 0.008-0.03 mg/L). More marked differences in activity were noted with S. pneumoniae, with MIC(90)s of 0.25, 1, 0.5 and 0.03 mg/L for moxifloxacin, levofloxacin, gatifloxacin and gemifloxacin, respectively. With the S. pneumoniae strains, the four fluoroquinolones exhibited similar concentration-dependent time-kill kinetics. The resistance selection frequencies of levofloxacin were higher than those of moxifloxacin at concentrations equivalent to those at the end of the dosing interval. Therefore moxifloxacin may have less of an impact on the development of resistance than levofloxacin.

Anti-Infective Agents↗

PubMed1994

Fluoroquinolone resistance among methicillin-resistant staphylococci after usage of fluoroquinolones other than ciprofloxacin in Taiwan.

The antimicrobial susceptibility to norfloxacin, ofloxacin, and ciprofloxacin of methicillin-resistant staphylococci isolated before and after the use of fluoroquinolones other than ciprofloxacin in Taiwan was studied by the agar dilution method. Before the use of fluoroquinolones, 54 isolates of methicillin-resistant Staphylococcus aureus (MRSA) and 51 isolates of methicillin-resistant coagulase-negative staphylococci (MRCNS) isolated in 1983-1985 were all susceptible to the three fluoroquinolones tested. Following the use of norfloxacin, enoxacin, and ofloxacin, the MIC90s of norfloxacin, ofloxacin, and ciprofloxacin against 46 isolates of MRSA collected during 1989-1990 increased to 64, 16, and 32 micrograms/ml, respectively, and the rates of resistant strains to these three agents were 37.0%, 30.4%, and 34.8%, respectively. The MIC90s against 42 isolates of MRCNS also increased to 64, 8, and 8 micrograms/ml, respectively, with 35.7%, 23.8%, and 33.3% resistant strains.

Anti-Infective Agents↗

PubMed2004

Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones.

The three topical ophthalmic fluoroquinolones recently introduced into the U.S. market--levofloxacin, gatifloxacin, and moxifloxacin--offer several advantages over the previously available fluoroquinolones (norfloxacin 0.3%, ciprofloxacin 0.3%, and ofloxacin 0.3%). These include enhanced spectrum and potency for Gram-positive cocci and possibly atypical mycobacterial species, improved penetration into the anterior segment, and reduced propensity to promote the development of resistance. Although published data and clinical experience with these agents is quite limited given their relatively recent entry into the U.S. market, this perspective will attempt to provide an understanding of the potential role of these newer fluorquinolones in addressing the problem of increasing fluoroquinolone resistance amongst bacterial ocular isolates.

Anti-Infective Agents↗

PubMed2000

Impact of fluoroquinolone administration on the emergence of fluoroquinolone-resistant gram-negative bacilli from gastrointestinal flora.

We assessed the risk factors for acquisition of fluoroquinolone-resistant, gram-negative organisms in the gastrointestinal tract of hospitalized patients. We analyzed stool samples from 204 patients and recovered fluoroquinolone-resistant, gram-negative organisms from 63. Receipt of fluoroquinolone during the month preceding admission was the only risk factor identified, whereas female sex, duration of hospitalization, exposure to indwelling devices, admission from another hospital, and history of infection were risk factors for fecal colonization after day 4.

Acinetobacter↗

PubMed2005

Cooperation between alteration of DNA gyrase genes and over-expression of MexB and MexX confers high-level fluoroquinolone resistance in Pseudomonas aeruginosa strains isolated from a patient who received a liver transplant followed by treatment with fluoroquinolones.

Clinical isolates of highly fluoroquinolone-resistant Pseudomonas aeruginosa had a mutation in either A or B subunit of DNA gyrase and over-expressed MexB and MexX, the efflux system proteins. Introduction of wild-type gyrase genes of Escherichia coli into the isolates made them as fluoroquinolonesusceptible as the moderately fluoroquinolone-resistant strains that only over-expressed efflux system proteins. These findings demonstrate that high fluoroquinolone-resistance in P. aeruginosa is attributed to cooperation between alteration in DNA gyrase genes and over-expression of efflux systems proteins.

Bacterial Outer Membrane Proteins↗

PubMed2001

Type II topoisomerase mutations in fluoroquinolone-resistant clinical strains of Pseudomonas aeruginosa isolated in 1998 and 1999: role of target enzyme in mechanism of fluoroquinolone resistance.

The major mechanism of resistance to fluoroquinolones for Pseudomonas aeruginosa is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV). We examined the mutations in quinolone-resistance-determining regions (QRDR) of gyrA, gyrB, parC, and parE genes of recent clinical isolates. There were 150 isolates with reduced susceptibilities to levofloxacin and 127 with reduced susceptibilities to ciprofloxacin among 513 isolates collected during 1998 and 1999 in Japan. Sequencing results predicted replacement of an amino acid in the QRDR of DNA gyrase (GyrA or GyrB) for 124 of the 150 strains (82.7%); among these, 89 isolates possessed mutations in parC or parE which lead to amino acid changes. Substitutions of both Ile for Thr-83 in GyrA and Leu for Ser-87 in ParC were the principal changes, being detected in 48 strains. These replacements were obviously associated with reduced susceptibilities to levofloxacin, ciprofloxacin, and sparfloxacin; however, sitafloxacin showed high activity against isolates with these replacements. We purified GyrA (The-83 to Ile) and ParC (Ser-87 to Leu) by site-directed mutagenesis and compared the inhibitory activities of the fluoroquinolones. Sitafloxacin showed the most potent inhibitory activities against both altered topoisomerases among the fluoroquinolones tested. These results indicated that, compared with other available quinolones, sitafloxacin maintained higher activity against recent clinical isolates with multiple mutations in gyrA and parC, which can be explained by the high inhibitory activities of sitafloxacin against both mutated enzymes.

Anti-Infective Agents↗