Toxicol Appl Pharmacol, 1996 Oct, 140(2), 254 - 63 Lack of effects of ciprofloxacin and the topoisomerase II inhibitors, m-AMSA and nalidixic acid, on DNA repair in cultured rat liver cells; Rosen JE et al.; Several quinolone antibiotics, including ciprofloxacin, have been reported to elicit autoradiographic unscheduled DNA synthesis (UDS) in cultured rat hepatocytes . In the present investigation, ciprofloxacin (CF), at 250-1500 microM, produced autoradiographic UDS in cultured rat hepatocytes, whereas neither the quinolone nalidixic acid nor m-AMSA, both topoisomerase II inhibitors, produced autoradiographic UDS . CF also reduced cytoplasmic {3H}thymidine levels ({3H}TdR) relative to control at 250-1500 microM and concomitantly increased nuclear grain counts accounting for most of the net increase yielding positive UDS values . To obtain definitive information on whether the positive UDS observed with CF was due to DNA repair, DNA repair synthesis was measured in parental DNA separated from newly replicated DNA using a bromodeoxyuridine incorporation density gradient method . This method was used to measure DNA repair synthesis in parental DNA of both replicating rat liver epithelial cells (ARL-18) and nonproliferating rat hepatocytes in primary culture . Primary hepatocytes exposed to CF from 250 to 1500 microM did not express DNA repair synthesis in parental DNA isolated by density gradient centrifugation but rather exhibited a concentration-related decrease in the level of {3H}TdR associated with DNA . In rat liver epithelial (ARL-18) cells, CF from 250 to 500 microM likewise did not elicit DNA repair synthesis and also caused a concentration-related decrease in the level of {3H}TdR associated with parental DNA . In contrast, in both cell types a substantial level of repair synthesis occurred in parental DNA as a result of exposure to 2-acetylaminofluorene, a DNA-reactive carcinogen, and in hepatocytes a similar finding was made for the drug hydralazine . Also, after induction of DNA repair in hepatocytes by ultraviolet light, the DNA polymerase alpha inhibitor aphidicolin almost completely abolished repair synthesis, whereas CF had a negligible effect on the inhibition of repair relative to control . These results indicate that CF did not elicit authentic DNA repair and also did not inhibit DNA repair synthesis . The fact that CF elicited autoradiographic UDS and that the topoisomerase II inhibitors m-AMSA and nalidixic acid did not indicates that effects on topoisomerase II are not the basis for the positive UDS result with CF as has been hypothesized in the past. Am J Ophthalmol, 1996 Oct, 122(4), 582 - 4 Intermediate uveitis and retinal vasculitis as manifestations of cat scratch disease; Soheilian M et al.; PURPOSE: To study the ocular manifestations of systemic Rochalimaea infection . METHODS: We examined a healthy 21-year old woman who had floaters in both eyes . A bilateral mild vitreitis and multiple foci of retinal vasculitis were found; during the ensuing two weeks, exudates appeared over the inferior pars plana . The patient owned five kittens but had no history of cat bites or scratches . Serum levels of antibodies to Rochalimaea were elevated . RESULT: The retinal vasculitis and vitreitis resolved after three weeks of therapy with ciprofloxacin hydrochloride without concomitant anti-inflammatory therapy . CONCLUSION: Rochalimaea infection should be considered in the differential diagnosis of intermediate uveitis and retinal vasculitis. Pharmacotherapy, 1996 Sep-Oct, 16(5), 937 - 41 Prospective validation of an optimal sparse plasma-sampling strategy for estimating ciprofloxacin pharmacokinetics; Amsden GW et al.; Data obtained from 23 critically ill patients treated with intravenous ciprofloxacin in two clinical trials were used to validate prospectively a previously developed maximum a posteriori (MAP)-Bayesian estimator and optimal plasma-sampling strategy (OSS) . Dosages ranged from 200 mg every 12 hours to 400 mg every 8 hours . Each patient had 8-16 samples taken, either as large gold standard sampling sets or as a mix of gold standard sets and OSSs . The MAP-Bayesian estimator used a two-compartment model and identified apparent volumes of distribution of the central and peripheral compartments, distributional clearance, and the slope and intercept of the relationship between creatinine clearance and total body clearance . Fit parameters were used to derive the apparent volume of distribution at steady state and the 24-hour area under the curve . All parameters derived from the OSS using the MAP-Bayesian estimates matched up almost identically to those obtained from modeling the gold standard sets . There was no systematic bias, and good precision was seen among all the parameters . These data demonstrate the usefulness and validity of the current OSS and MAP-Bayesian estimator, and provide further evidence of the utility of optimal sampling theory. Antimicrob Agents Chemother, 1996 Sep, 40(9), 2126 - 30 Intestinal elimination of ofloxacin enantiomers in the rat: evidence of a carrier-mediated process; Rabbaa L et al.; The aim of this work was to examine the mechanism involved in intestinal elimination of the two optical isomers of ofloxacin in the rat . An intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery . Blood samples and intestinal effluents were collected and analyzed by a high-performance liquid chromatography method . We observed saturable and stereoselective intestinal elimination of the ofloxacin enantiomers . The elimination process favored the R-(+) form of the molecule . After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, intestinal clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively . Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the intestinal clearance of S-(-)- and R-(+)-ofloxacin . With concomitant ciprofloxacin, intestinal clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14 +/- 0.01 versus 0.19 +/- 0.05 ml/min with pefloxacin for S-(-)- and R-(+)-ofloxacin, respectively . Those findings argue for the presence of a common transport system in the rat intestine with variable affinities for fluoroquinolones . In addition, verapamil and quinidine, two P-glycoprotein blockers, significantly reduced the intestinal elimination of both ofloxacin isomers (with concomitant verapamil, intestinal clearances were 0.12 +/- 0.02 versus 0.18 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively, while with concomitant quinidine, values were 0.18 +/- 0.01 versus 0.23 +/- 0.01 ml/min without modifying their areas under the concentration-time curve in serum . Similar results were found with another fluoroquinolone, ciprofloxacin, in previous work . P-glycoprotein appears to be involved in the intestinal elimination of fluoroquinolones in rats . The characterization of fluoroquinolone intestinal elimination has significant clinical relevance for the better evaluation of the influence of this secretory pathway on antibiotic efficacy and selection of resistant bacteria within the intestinal flora. J Dermatol, 1996 Aug, 23(8), 530 - 4 Drug related involvement of specific sites in fixed eruptions: a statistical evaluation; Sharma VK et al.; Different drugs produce fixed eruptions over different parts of the body . However, the significance of preferential site involvement in fixed eruptions due to specific drugs has not been statistically evaluated . One hundred and twenty five patients of fixed drug eruption (FDE) were studied to examine this question . Different sites affected by individual drugs were classified as lips alone, genitalia alone, lips and genitalia together, trunk alone, trunk and limbs together, and generalized . Statistical analysis was carried out for 7 common drugs causing FDE in 5 or more patients . Cotrimoxazole, a combination of sulfamethoxazole and trimethoprim, was the most common offender for FDE (32.8%), followed by analgin (12%), tetracycline (8%), pyrazolones (8%), metronidazole (6.4%), ciprofloxacin (5.6%), and phenytoin sodium (4%) . Major sites involved by FDE were trunk and limbs (24%), lips alone (20.8%), genitalia alone (20%), generalised (14.4%), lips and genitalia together (11.2%), and trunk alone (8.8%) . Seventy-two (57.6%) patients had multiple lesions; 33 (42.4%) had single lesions . Involvement of mucocutaneous junctions of lips and genitalia by FDE was frequently caused by cotrimoxazole and tetracycline; trunk and limbs, by analgin and pyrazolones . Generalised eruptions were commonly caused by cotrimoxazole and phenytoin . The present statistical analysis confirms the clinical impression that genitalia alone are frequently involved in FDE due to tetracyclines (p < 0.001) . FDE over trunk and limbs was significantly associated with analgin (p < 0.001), and generalised eruptions, with phenytoin sodium (p < 0.001) . The association of FDE over lips with cotrimoxazole was statistically not significant. Antimicrob Agents Chemother, 1996 Aug, 40(8), 1860 - 5 Development and evaluation of a Bayesian pharmacokinetic estimator and optimal, sparse sampling strategies for ceftazidime; Kashuba AD et al.; Data were gathered during an activity-controlled trial in which seriously ill, elderly patients were randomized to receive intravenous ceftazidime or ciprofloxacin and for which adaptive feedback control of drug concentrations in plasma and activity profiles was prospectively performed . The adaptive feedback control algorithm for ceftazidime used an initial population model, a maximum a posteriori (MAP)-Bayesian pharmacokinetic parameter value estimator, and an optimal, sparse sampling strategy for ceftazidime that had been derived from data in the literature obtained from volunteers . Iterative two-stage population pharmacokinetic analysis was performed to develop an unbiased MAP-Bayesian estimator and updated optimal, sparse sampling strategies . The final median values of the population parameters were follows: the volume of distribution of the central compartment was equal to 0.249 liter/kg, the volume of distribution of the peripheral compartment was equal to 0.173 liter/kg, the distributional clearance between the central and peripheral compartments was equal to 0.2251 liter/h/kg, the slope of the total clearance (CL) versus the creatinine clearance (CLCR) was equal to 0.000736 liter/h/kg of CL/1 ml/min/1.73 m2 of CLCR, and nonrenal clearance was equal to + 0.00527 liter/h/kg . Optimal sampling times were dependent on CLCR; for CLCR of > or = 30 ml/min/1.73 m2, the optimal sampling times were 0.583, 3.0, 7.0, and 16.0 h and, for CLCR of < 30 ml/min/1.73 m2, optimal sampling times were 0.583, 4.15, 11.5, and 24.0 h . The study demonstrates that because pharmacokinetic information from volunteers may often not be reflective of specialty populations such as critically ill elderly individuals, iterative two-stage population pharmacokinetic analysis, MAP-Bayesian parameter estimation, and optimal, sparse sampling strategy can be important tools in characterizing their pharmacokinetics. Antimicrob Agents Chemother, 1996 Aug, 40(8), 1855 - 9 Trovafloxacin is active against Toxoplasma gondii; Khan AA et al.; Drugs currently used for treatment of toxoplasmosis in pregnant women, congenital infections, immunocompromised patients, and patients with the ocular disease are not always effective or may be dangerous to use; therefore, there is a need for more-effective and less-toxic drugs . Recently, we examined a group of fluoroquinolones for in vitro and in vivo activities against Toxoplasma gondii . Among those examined in vitro (ciprofloxacin, fleroxacin, ofloxacin, temafloxacin, and trovafloxacin), only trovafloxacin significantly inhibited intracellular replication of T . gondii without significant toxicity for host cells . In a murine model of acute toxoplasmosis, 100 or 200 mg of trovafloxacin per kg of body weight per day for 10 days protected 100% of infected mice against death . A dose of 50 mg/kg/day protected 90% of the mice, and a dose of 25 mg/kg/day effected prolongation of time to death . The other fluoroquinolones did not have such in vivo activities . These results indicate that trovafloxacin may be useful for treatment of toxoplasmosis in humans. Antimicrob Agents Chemother, 1996 Aug, 40(8), 1790 - 5 Detection of rifampin- and ciprofloxacin-resistant Mycobacterium tuberculosis by using species-specific assays for precursor rRNA; Cangelosi GA et al.; rRNA precursor (pre-rRNA) molecules carry terminal stems which are removed during rRNA synthesis to form the mature rRNA subunits . Their abundance in bacterial cells can be markedly affected by antibiotics which directly or indirectly inhibit RNA synthesis . We evaluated the feasibility of rapidly detecting antibiotic-resistant Mycobacterium tuberculosis strains by measuring the effects of brief in vitro antibiotic exposure on mycobacterial pre-rRNA . By hybridizing extracted M . tuberculosis nucleic acid with radiolabeled nucleic acid probes specific for pre-16S rRNA stem sequences, we detected clear responses to rifampin and ciprofloxacin within 24 and 48 h, respectively, of exposure of cultured cells to these drugs . Detectable pre-rRNA was depleted in susceptible cells but remained abundant in resistant cells . In contrast, no measurable responses to isoniazid or ethambutol were observed . Probes for pre-rRNA were specific for the M . tuberculosis complex when tested against a panel of eight Mycobacterium species and 48 other bacteria . After 24 h of incubation with rifampin, resistant M . tuberculosis strains were detectable in a reverse transcriptase PCR assay for pre-rRNA with a calculated lower limit of sensitivity of approximately 10(2) cells . Susceptible cells were negative in this assay at over 500 times the calculated lower limit of sensitivity . This general approach may prove useful for rapidly testing the susceptibility of slowly growing Mycobacterium species to the rifamycin and fluoroquinolone drugs and, with possible modifications, to other drugs as well. Kekkaku, 1996 Aug, 71(8), 453 - 8 {Determination of antimycobacterial activities of fluoroquinolones against clinical isolates of Mycobacterium tuberculosis: comparative determination with egg-based Ogawa and agar-based Middlebrook 7H10 media}; Yamane N et al.; The minimum inhibitory concentrations (MICs) to the fluoroquinolones, ofloxacin (OFLX), ciprofloxacin (CPFX), sparfloxacin (SPFX), norfloxacin (NFLX), balofloxacin (BLFX) and CS-940, were determined in 100 clinical isolates of Mycobacterium tuberculosis . The MICs were determined with 1% egg-based Ogawa or agar-based Middlebrook 7H10 and each of them supplemented with oxidation-reduction color dye, 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride (STC) by using the microculture technique . The MICs determined with Ogawa medium were approximately two- to four-fold higher when compared to those determined with Middlebrook agar medium . The supplement with STC slightly increased the MICs, probably as a result of easily recognizing small initial colonies . Among the six fluoroquinolones, CS-940 and SPFX showed the greatest antimycobacterial activities with inhibition of 50% of all the isolates at the concentrations between 0.25 to 0.5 microgram/ml . OFLX, CPFX and BLFX followed in potency at 0.5 to 2.0 micrograms /ml . NFLX was less potent requiring 8 to 16 micrograms/ml to inhibit 50% of the isolates. Zentralbl Veterinarmed A, 1996 Aug, 43(6), 377 - 86 Disposition of enrofloxacin (Baytril) into the udder after intravenous and intra-arterial injections into dairy cows; Malbe M et al.; Enrofloxacin (Baytril) was injected into arteries supplying the udder of dairy cows . The idea was to avoid primary distribution, metabolism and elimination and thus to deliver the drug to the target organ at higher concentration . Enrofloxacin injected into the abdominal aorta or the external iliac artery resulted in high initial enrofloxacin retention by the udder and high milk concentrations . Injection of enrofloxacin into the abdominal aorta resulted in 2.2 times higher milk peak concentration of the drug than intravenous injection into the jugular vein . Injection of the drug into one of the two external iliac arteries allowed drug concentrations of milk from the udder halves to be compared: when enrofloxacin was injected into the right external iliac artery, the peak milk enrofloxacin concentration from the right udder half was 4.8 times that of the left udder half . The bulk of enrofloxacin was absorbed from the milk compartment of the udder before the next regular milking 6.5 h later . By this time, the metabolite ciprofloxacin had accumulated in milk . Pharmacokinetic values for enrofloxacin and its metabolite ciprofloxacin are given separately for serum and milk whey following three intravascular dosing routes. Therapie, 1996 Jul-Aug, 51(4), 414 - 6 Adverse drug reactions with fluoroquinolones; Royer RJ; The French system of drug surveillance has analysed the notifications of adverse drug reactions (ADRs) to fluoroquinolones since they were launched . Their frequency ranges from 1/15,000 to 1/208,000 case per days of treatment . Cutaneous diseases and tendon disorders predominate in France whereas cutaneous effects and neuropsychiatric disorders are predominant in the UK; tendon disorders take up only the 5th position . Among the most unexpected ADRs are the following: -shock represents 33 of the anaphylaxis reactions which range from 1/5.6 x 10(6) to 1/4.4 x 10(5) case per days of treatment . -acute renal failure is rare: one case/80,000 patients treated by ciprofloxacin to 1/320,000 by norfloxacin . The pathophysiology is not well known . Tendon ruptures represent 81 cases for 921 notifications of tendon disorders which are related in decreasing order to pefloxacin 1/23,130 case per days of treatment, ofloxacin, norfloxacin and ciprofloxacin 1/779,600 case per days of treatment . Age and corticosteroids increase the risk of tendon rupture. APMIS, 1996 Jul-Aug, 104(7-8), 531 - 8 Cefuroxime resistance in Escherichia coli . Resistance mechanisms and prevalence; Schumacher H et al.; In order to characterize cefuroxime resistance in Escherichia coli 22 clinical isolates were investigated for susceptibility to different beta-lactam antibiotics and ciprofloxacin . The production of beta-lactamases, the pattern of the major outer membrane proteins (OMPs), and the plasmid profiles were determined for these isolates . Ten of the isolates were resistant to ceftazidime, two to cefotaxime, and none was resistant to imipenem or ciprofloxacin . The dominating resistance mechanism was hyperproduction of the chromosomally encoded beta-lactamase to some extent accompanied by alterations of the OMP's . Two isolates with low ampicillin MIOs seemed solely to have alteration of the OMPs . None of the isolates produced plasmid-mediated extended-spectrum beta-lactamases . In addition, the prevalence of cefuroxime resistance was investigated . The prevalence as attained in 8704 clinical isolates of E . coli collected from Copenhagen County during a 5-year period (1990-1994) was 4.4%, but there was considerable variation among specimens from different sites of the body . Isolates from blood were much less resistant (2.5%) than isolates from the respiratory tract (9.7%). Eur J Ophthalmol, 1996 Jul-Sep, 6(3), 287 - 92 Comparative evaluation of efficacy and safety of ciprofloxacin and norfloxacin ophthalmic solutions; Adenis JP et al.; The efficacy and safety of ciprofloxacin ophthalmic solution 0.3% and norfloxacin ophthalmic solution 0.3% in the treatment of bacterial conjunctivitis and blepharitis were compared in a double masked randomised study . A total of 131 patients, 65 treated with ciprofloxacin (42 with conjunctivitis and 23 with blepharitis) and 66 treated with norfloxacin (39 with conjunctivitis and 27 with blepharitis) were enrolled in the study at five centres in France . In the efficacy population, pathogens were eradicated or reduced in 96% (24/25) of patients in the ciprofloxacin group and 89% (24/27) in the norfloxacin group . There was no difference between treatments with regard to eradication of particular pathogens . In the efficacy population, clinical cure or improvement was seen in 96% of the patients (24/25 in the ciprofloxacin group and 26/27 in the norfloxacin group) . There were no significant differences between ciprofloxacin and norfloxacin with respect to improvements in four symptoms or ten clinical signs . No serious treatment-related adverse events were reported and both ciprofloxacin and norfloxacin were well tolerated. J Antimicrob Chemother, 1996 Jul, 38(1), 139 - 43 Effect of ciprofloxacin on ciliary motility of rabbit airway epithelium; Takemura H et al.; To determine the effect of the new quinolone ciprofloxacin on airway ciliary motility, we studied ciliary beat frequency (CBF) of rabbit tracheal epithelium using an in-vitro microphoto-oscillation method . Incubation of the cells with ciprofloxacin increased CBF in a concentration-dependent manner, the maximal increase from the baseline value and the EC50 being 17.1 +/- 2.0% (P < 0.01) and 10(-7.25) M, respectively . This ciliary stimulatory effect was not affected by propranolol or indomethacin but was nullified by verapamil . These results suggest that ciprofloxacin probably increases airway epithelial ciliary motility by facilitating Ca2+ influx through a voltage-dependent channel. J Int Med Res, 1996 Jul-Aug, 24(4), 345 - 51 Effect of pyridone carboxylic acid anti-microbials on the generation of reactive oxygen species in vitro; Akamatsu H et al.; The effects of ofloxacin, ciprofloxacin and balofloxacin on the reactive oxygen species (ROS) levels generated by human neutrophils was examined in vitro; ROS generated in a cell-free, xanthine-xanthine oxidase system was also assessed . The species investigated were superoxide radical anion (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OH*) . Both ofloxacin and ciprofloxacin markedly decreased the levels of O2-, H2O2 and OH* generated by human neutrophils . On the other hand, these drugs did not affect any of the ROS examined in the xanthine-xanthine oxidase system . Balofloxacin showed no significant effect on ROS generated by either system . The present study indicates that ofloxacin and ciprofloxacin may exert an anti-inflammatory action by reducing the potent ROS species excessively generated by neutrophils at the sites of inflammation. Clin Infect Dis, 1996 Jul, 23(1), 173 - 5 Cutaneous and pulmonary infections caused by Mycobacterium vaccae; Hachem R et al.; Mycobacterium vaccae is a rapidly growing mycobacterial species that was previously not considered a human pathogen . We report four cases of M . vaccae infection that occurred in the southern United States; one patient had cutaneous disease, and three patients had cavitary lung disease . Two of the three patients with pulmonary disease had a history of exposure to cattle . The conditions of all patients improved with therapy: the cutaneous infection responded to therapy with minocycline and trimethoprim-sulfamethoxazole, and the pulmonary infections responded to therapy with ciprofloxacin. Antimicrob Agents Chemother, 1996 Jul, 40(7), 1715 - 6 Effect of combination therapy with ciprofloxacin and clarithromycin on theophylline pharmacokinetics in healthy volunteers; Gillum JG et al.; Five adults completed this four-way randomized crossover study to compare the effects of oral treatment with ciprofloxacin, clarithromycin, and a combination of the two drugs on theophylline pharmacokinetics . The area under the concentration-time curve for theophylline during combination therapy was not different from that for ciprofloxacin alone . Beta error may explain this finding, but any real effect from combination treatment appears to be clinically unimportant. Antimicrob Agents Chemother, 1996 Jul, 40(7), 1617 - 22 Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects; Conte JE Jr et al.; The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g) . In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration . Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography . Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method . The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h) . None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy . The movement into and persistence in cells was different for azithromycin and clarithromycin . In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1) . The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin . 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml) . The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1 . The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF . The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies. J Bacteriol, 1996 Jul, 178(13), 3791 - 5 Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump; Liu J et al.; The lfrA gene cloned from chromosomal DNA of quinolone-resistant Mycobacterium smegmatis mc2-552 conferred low-level resistance to fluoroquinolones when present on multicopy plasmids . Sequence analysis suggested that lfrA encodes a membrane efflux pump of the major facilitator family (H . E . Takiff, M . Cimino, M . C . Musso, T . Weisbrod, R . Martinez, M . B . Delgado, L Salazar, B . R . Bloom, and W . R . Jacbos, Jr., Proc . Natl . Acad . Sci . USA 93:362-366, 1996) . In this work, we studied the role of LfrA in the accumulation of fluoroquinolones by M . smegmatis . The steady-state accumulation level of a hydrophilic quinolone, norfloxacin, by M . smegmatis harboring a plasmid carrying the lfrA gene was about 50% of that by the parent strain but was increased to the same level as that of the parent strain by addition of a proton conductor, carbonyl cyanide m-chorophenylhydrazone . Norfloxacin efflux mediated by LfrA was competed for strongly by ciprofloxacin but not by nalidixic acid . Furthermore, we showed that portions of norfloxacin accumulated by starved cells were pumped out upon reenergization of the cells, and the rates of this efflux showed evidence of saturation at higher intracellular concentrations of the drug . These results suggest that the LfrA polypeptide catalyzes the active efflux of several quinolones. Schweiz Med Wochenschr, 1996 Jun 15, 126(24), 1062 - 5 {Disseminated infection with Mycobacterium celatum}; Emler S et al.; A 29-year-old patient with AIDS was hospitalized with weight loss, fever and cough . Mycobacterial cultures from sputum, blood and bronchoalveolar lavage became positive after 3 weeks' incubation . When using a DNA probe for identification of Mycobacterium tuberculosis complex, a weakly positive signal was obtained . Tuberculosis was suspected and treatment was started with isoniazid, ethambutol and ciprofloxacin . Sequencing of the gene of the 16S rRNA, however, identified the isolates as belonging to a new, slow-growing atypical mycobacterial species, Mycobacterium celatum (M . celatum) . Treatment was modified to take into account the previously described primary resistance of M . celatum to antituberculous drugs, whereupon the patient improved. Mutat Res, 1996 Jun 10, 352(1-2), 143 - 50 In vitro induction of micronuclei and chromosome aberrations by quinolones: possible mechanisms; Curry PT et al.; The bacterial gyrase inhibitors, ciprofloxacin and PD 124816, were tested for clastogenic and aneugenic activity in V79 Chinese hamster lung cells in vitro . Cells were exposed for 3 h, washed free of drug, and subcultured for assessment of various endpoints . For structural chromosomal aberration (SCA) analysis, cells were incubated for 18 h, and treated with Colcemid for 2 h before harvest . For micronucleus (MN) analysis, treated cells were incubated with cytochalasin B (CYB) for 16 h . Aneugenicity was assessed by utilizing antikinetochore antibody to detect kinetochore-containing (K +) MN . Both quinolones induced significant increases in SCAs and MN, indicating clastogenic activity . With both compounds, however, the MN response was apparent at lower doses, and remained much higher throughout the dose range than the SCA response . The induced MN were predominantly K --, indicating that aneugenicity was not playing a major role in their induction . A possible explanation for the chromosome effects is that cross-reactivity of the gyrase inhibitors with mammalian topoisomerase II interferes with the separation of chromatids at anaphase leading to chromosome breaks and MN . Quinolones are known to inhibit resolution of the normally transient topoisomerase II-DNA cleavable complex, which may result in chromosome stickness . Thus, SCAs detected in metaphase cells may be attributed to quinolone-induced inhibition of topoisomerase II prior to mitosis while MN arise in binucleated cells as a result of this effect which interferes with chromatid separation during anaphase. Am J Ophthalmol, 1996 Jun, 121(6), 712 - 5 Fluoroquinolones in the treatment of bacterial keratitis; Bower KS et al.; PURPOSE: We evaluated the potential role of three topical fluoroquinolones in the treatment of bacterial keratitis by means of a laboratory database . METHODS: Antibiotic susceptibilities were determined for 153 isolates from patients with bacterial keratitis . Results were analyzed for each fluoroquinolone individually and in combination with cefazolin . RESULTS: Predicted susceptibility to each cefazolin-fluoroquinolone combination (98.7%) was superior to that for single-agent therapy with ofloxacin (88.2%), ciprofloxacin (82.3%), or norfloxacin (80.4%) (P = .0002) . A cefazolin-fluoroquinolone combination (98.7%) was comparable to a cefazolin-gentamicin combination (97.4%) . CONCLUSIONS: Combination therapy with cefazolin and a fluoroquinolone offers a reasonable alternative for the treatment of bacterial keratitis . Single-agent therapy with fluoroquinolones for vision-threatening bacterial keratitis is not advised. Tidsskr Nor Laegeforen, 1996 May 20, 116(13), 1577 - 80 {Treatment of uncomplicated gonorrhea in adults . New guidelines from the working group against gonorrhea}; Aavitsland P et al.; Only 229 cases of gonococcal infection were recorded in Norway in 1994 (population 4.3 million), as against more than 14,000 cases two decades before . Up to now aminopenicillins with probenecid have been the standard treatment . In 1994, 29% of the reported cases of gonococcal infection were caused by a betalactamase-producing strain . We now recommend treating uncomplicated gonococcal infections with a single oral dose of ciprofloxacin 500 mg, or ofloxacin 400 mg . Pregnant or lactating women should receive intramuscular injections of cefotaxim 500 mg, or spectinomycin 2 g . Test-of-cure is essential . Its main purpose is to discover resistant strains and reinfections . Thorough contact tracing is more important than ever . Culture verification, susceptibility testing and test-of-cure in all cases will influence the continuous reevaluation of these guidelines. Acta Otorrinolaringol Esp, 1996 May-Jun, 47(3), 217 - 20 {Prospective double-blind randomized study of the efficacy and tolerance of topical ciprofloxacin vs topical gentamicin in the treatment of simple chronic otitis media and diffuse external otitis}; Sabater F et al.; A prospective, randomized double-blind study was made of topical ciprofloxacillin (0.5%) compared with topical gentamicin (0.3%) in the treatment of simple chronic otitis media (COM) and diffuse external otitis (DEO) . The study included 47 patients with COM and 54 patients with DEO . Success rates in the COM subgroup were 95% for ciprofloxacillin and 96% for gentamicin (p = 0.082), and in the DEO subgroup, 87% for ciprofloxacillin and 79% for gentamicin (p = 0.19) . Both drugs were well tolerated and there was no significant change in audiometric measurements with either medication in either group . Therefore, ciprofloxacillin is at least as effective as gentamicin in such ear infections and has no potential ototoxic effect. J Antimicrob Chemother, 1996 May, 37 Suppl A, 41 - 55 Pharmacokinetic interactions related to the chemical structures of fluoroquinolones; Mizuki Y et al.; Fluoroquinolone derivatives interact with methylxanthines (theophylline, caffeine) and metallic ion-containing drugs to different degrees . The rat appears to be a suitable model for predicting such interactions in man . It has been possible to determine the relationship between the chemical structure of the fluoroquinolone and the magnitude of the interaction . Fluoroquinolones with a bulky substituent at the position 8, such as sparfloxacin, lomefloxacin and fieroxacin, are less prone to interact with theophylline than those without an 8-substituent, such as enoxacin . This substituent determines the planarity of the whole fluoroquinolone molecule and the interaction tends to be more significant for planar fluoroquinolones . Furthermore, a 4'-nitrogen atom in the 7-piperazinyl group is essential for the interaction to occur . The nitrogen atom is possibly the site that binds cytochrome P-450, which catalyses theophylline metabolism . The reduction in bioavailability of fluoroquinolones by concurrent administration of aluminium hydroxide is more striking for derivatives with fewer substituents on the essential structure and on the piperazinyl group, such as norfloxacin, ciprofloxacin and enoxacin . Substitution at the 5-position diminishes the interaction, which suggests that the 5-substituent may affect the formation and/or stability of unabsorbable chelate complex which is the probable cause of the interaction . These findings are potentially useful in designing fluoroquinolones less prone to drug interactions. Clin Infect Dis, 1996 May, 22(5), 827 - 33 Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis; Kennedy N et al.; The fluoroquinolones are promising new antituberculous agents . A randomized controlled trial of 200 adult patients with sputum smear-positive pulmonary tuberculosis was conducted in Tanzania . Patients received either a trial regimen (HRC) consisting of isoniazid (300 mg), rifampin (600 mg), and ciprofloxacin (750 mg) or a control regimen (HRZE) consisting of isoniazid (300 mg), rifampin (600 mg), pyrazinamide (25 mg/kg), and ethambutol (15 mg/kg) . The 168 evaluable patients all had negative smears and cultures by month 6, but the time to conversion to negativity was longer for the HRC group than for the HRZE group because of the poor response of patients infected with human immunodeficiency virus (HIV) to the HRC regimen . Relapse was more frequent in the HRC group . The sterilizing activity of ciprofloxacin does not appear to be equal to that of the combination of pyrazinamide and ethambutol, but the difference in outcome was significant only among HIV-infected patients. Antibiot Khimioter, 1996 Apr, 41(4), 51 - 3 {Effect of drugs of the fluoroquinolone series on morphokinetic parameters of the cellular elements of lung tissue}; Kunichan AD et al.; The effect of various concentrations of ofloxacin, ciprofloxacin and lomefloxacin on the morphokinetic parameters of the cellular elements of the lung tissue of intact animals (mice, guinea pigs and dogs) was studied under the conditions of the tissue culture . It was shown that in a concentration of 100 micrograms/ml and the exposure time of 24 hours the drugs had no effect on the mobility and structure of the lung tissue cellular elements . When the drugs were used in a concentration of 100 micrograms/ml the mobility rate of the lymphocytes and macrophages proved to by markedly retarded by the end of the 24th hour . In a concentration of 1000 micrograms/ml the drugs killed the cell culture . There were detected no specific differences in the effect of the fluoroquinolones on the cellular elements of the lung tissue of the intact animals. Antimicrob Agents Chemother, 1996 Apr, 40(4), 870 - 3 Sequence of quinolone resistance-determining region of gyrA gene for clinical isolates and for an in vitro-selected quinolone-resistant strain of Coxiella burnetii; Musso D et al.; We report the sequence of the quinolone resistance-determining region of the gyrA genes of either susceptible or low-level-resistant clinical isolates of Coxiella burnetii . The sequences of low-level (MICs, 4 micrograms/ml) and high-level (MICs, 8 and 16 micrograms/ml) resistant strains stepwise selected in vitro were also determined . The gene sequences of all of the clinical isolates and that of the in vitro-selected low-level-resistant strain were identical . Sequence analysis of the in vitro-selected high-level-resistant strain revealed a nucleotide mutation leading to an amino acid substitution of Gly in place of Glu at position 87 of the GyrA amino acid sequence . These results indicate that high-level resistance to ciprofloxacin is associated with a nucleotide mutation in gyrA, whereas low-level resistance to quinolones is not. Ann Pharmacother, 1996 Apr, 30(4), 364 - 6 Possible pharmacokinetic interaction with quinidine: ciprofloxacin or metronidazole? Cooke CE, Sklar GE, Nappi JM. OBJECTIVE: To discuss a potential pharmacokinetic interaction between quinidine, ciprofloxacin, and metronidazole . CASE SUMMARY: A 51-year-old black woman was admitted for shortness of breath, abdominal pain, and atrial fibrillation . Procainamide and diltiazem were begun for the atrial fibrillation and ciprofloxacin and metronidazole for suspected diverticulitis . The therapy was switched to quinidine on day 5 because of adverse events associated with procainamide . A trough serum quinidine concentration (SQC) on day 7 was 6.3 micrograms/mL (normal 2-5) with normal QT and QTc intervals . On day 8, the patient was discharged in normal sinus rhythm . She took her last doses of antibiotics on day 15 and a follow-up SQC on day 18 was 2.3 micrograms/mL . DISCUSSION: The possible explanations for the changes in SQCs include: (1) laboratory error, (2) compliance with medication regimen, and (3) altered hepatic metabolism . The first two are not likely in this case . The laboratory verified the elevated SQC and the patient had her prescriptions refilled within appropriate time limits . The third explanation seems more plausible . Quinidine is metabolized by the hepatic mixed-function oxidase system, specifically cytochrome P450 (CYP) 3A4 . We found that metronidazole has been shown to inhibit CYP3A activity and ciprofloxacin has been shown to inhibit certain isozymes in the cytochrome P450 system as well . CONCLUSIONS: When metronidazole and ciprofloxacin are administered concomitantly with quinidine, clinicians should be aware of this potential interaction . Quinidine concentrations should be monitored and patients should be assessed for signs and symptoms of quinidine toxicity. Am J Vet Res, 1996 Apr, 57(4), 547 - 53 Penetration of enrofloxacin and ciprofloxacin into breast milk, and pharmacokinetics of the drugs in lactating rabbits and neonatal offspring; Aramayona JJ et al.; OBJECTIVE--To determine the pharmacokinetics and milk penetration of enrofloxacin (ENR) and ciprofloxacin (CIP) in lactating rabbits and their disposition in suckling rabbits . DESIGN--Prospective cross-over study . ANIMALS--6 lactating New Zeland White rabbits and their offspring (16 days after parturition) . PROCEDURE--Serial plasma and milk samples were assayed by use of a high-performance liquid chromatography technique . In vitro protein binding in plasma and skim milk was measured by ultrafiltration . Skim-to-whole milk ratio also was determined . The time course of ENR and CIP was fitted by nonlinear least squares regression analysis, and the pharmacokinetic variables were compared . RESULTS--The time courses of ENR and CIP in plasma were similar in lactating adult rabbits (mean body clearances, 23.9 and 27.2 ml/min/kg of body weight, for ENR and CIP, respectively) . Observed milk-to-plasma ratios (M/P) were determined, using the area under the milk and plasma concentration versus time profiles (ENR, 2.59; CIP, 3.61) . Predicted M/P (ENR, 6.35; CIP, 3.04) were calculated from in vitro measurements . Body clearance calculated for ENR and CIP in suckling rabbit pups involved a decrease of 80 and 74%, respectively, over that found in lactating animals . CONCLUSIONS--Observed CIP M/P were correlated to predicted values, which strengthens the argument that CIP passes into the milk by nonionic diffusion . The lack of correlation between observed and predicted ENR M/P pointed out that ENR undergoes faster elimination from milk than that predicted by the diffusional model . Diminished elimination capacity observed in suckling rabbits would result in greater exposure than that predicted from concentrations alone. Gastroenterology, 1996 Apr, 110(4), 1150 - 5 Effects of hepatic stimulator substance, herbal medicine, selenium/vitamin E, and ciprofloxacin on cirrhosis in the rat; Zhang M et al.; BACKGROUND & AIMS: Cirrhosis is a potentially lethal condition for which there is no proven effective therapy . The aim of this study was to compare the effects of hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin treatment on biochemical and histological features of fibrosis in rats with carbon tetrachloride (CCl4)/ethanol-induced cirrhosis . METHODS: One hundred twenty adult Wistar rats were divided into six study groups (20 rats/group): healthy controls, CCl4/ethanol-injured rats left untreated, and CCl4/ethanol-injured rats treated for 4 weeks with either hepatic stimulator substance, traditional Chinese herbal medicine, a combination of selenium plus vitamin E, or ciprofloxacin . After the 4-week treatment, rats were killed and the following parameters of hepatic fibrosis were determined: hepatic hydroxyproline and proline levels, serum hyaluronic acid concentrations, and histological staining of hepatic tissue . RESULTS: Hepatic fibrosis was significantly improved in all four treated groups compared with the untreated CCl4/ethanol-injured controls . Improvements were most striking in the groups treated with traditional Chinese herbal medicine and ciprofloxacin . CONCLUSIONS: The data indicate that hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin significantly decrease the amount of hepatic fibrosis caused by CCl4/ethanol injury in rats. Clin Pharmacol Ther, 1996 Apr, 59(4), 418 - 22 Iron-ovotransferrin preparation does not interfere with ciprofloxacin absorption; Pazzucconi F et al.; Iron supplements can interfere with the bioavailability of a number of drugs, including thyroxine, tetracycline derivatives, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, and the newer fluoroquinolones . A new iron formulation was tested in which iron ions are bound to ovotransferrin, a protein that shares more than an 80% similarity with the sequence of human transferrin and apparently is less likely than the commonly used iron salts to reduce drug absorption . Ciprofloxacin was taken as a model drug, of wide use and restricted range of therapeutic levels, and its absorption was evaluated after the administration of the iron-ovotransferrin complex versus an iron-gluconate formulation in healthy volunteers . At variance with the iron gluconate formulation, which led to a reduction of about 50% of peak serum ciprofloxacin levels (Cmax; 1.0 +/- 0.2 versus 2.4 +/- 0.3 micrograms/ml; p < 0.01) and of the area under the serum concentration-time curve from time 0 to infinity {AUC(0 - infinity); 10.1 +/- 1.1 versus 18.3 +/- 1.0 mg.L-1.hr; p < 0.01}, the iron-ovotransferrin complex caused only modest, non significant changes in absorption with a minimal reduction of the AUC{0 - infinity) (17.3 +/- 1.0 versus 18.3 +/- 1.0 mg.L-1.hr; difference not significant) and a nonsignificant decrease in the Cmax (2.2 +/- 0.3 versus 2.4 +/- 0.3 microgram/ml; difference not significant) . Iron was also well absorbed from the formulation in the presence of a fatty meal . The very common drug interactions with oral iron preparations can be effectively prevented by the use of the iron-ovotransferrin complex interacting to a minimal extent with a sensitive drug with a reduced margin of efficacy, such as ciprofloxacin. Antimicrob Agents Chemother, 1996 Mar, 40(3), 787 - 91 Penetration of ciprofloxacin and fleroxacin into biliary tract; Edmiston CE Jr et al.; Forty patients with chronic cholecystitis or cholelithiasis were prospectively randomized for therapy with either ciprofloxacin or fleroxacin to study the penetration of these two agents into gallbladder tissue, plasma, and bile . Patients received a 3-day course of ciprofloxacin (500 mg twice a day) or fleroxacin (400 mg once daily) and were subdivided into four groups reflecting intraoperative sample collection at 4, 7, 14, and 25 to 26 h following the last quinolone dose . Mean concentrations in plasma for ciprofloxacin and fleroxacin at 4 and 25 to 26 h postdose were 2.5 and 10 micrograms/ml and 0.3 and 1.8 micrograms/ml, respectively . The concentrations of ciprofloxacin and fleroxacin in bile and gallbladder wall tissue at 25 to 26 h postdose were 4.5 and 8.6 micrograms/ml and 1.2 and 4.4 micrograms/ml, respectively . Both agents demonstrate rapid tissue penetration with persistence at levels appropriate for treatment of biliary pathogens. Pharmacotherapy, 1996 Mar-Apr, 16(2), 314 - 6 Failure of prostatitis treatment secondary to probable ciprofloxacin-sucralfate drug interaction; Spivey JM et al.; Metal cations such as aluminum, magnesium, ferrous sulfate, and zinc are thought to form chelation complexes with fluoroquinolone antibiotics and prevent the drugs from being absorbed . Sucralfate, which has a high aluminum content, reduces the bioavailability of ciprofloxacin to approximately 4% . The concomitant administration of ciprofloxacin and sucralfate resulted in treatment failure for a patient with prostatitis and a subsequent 5-day hospitalization . Fluoroquinolone antibiotics should be administered at least 2 hours before agents containing metal cations to allow for their absorption . In addition, sucralfate should not be administered less than 6 hours before fluoroquinolone antibiotic administration. J Pharm Biomed Anal, 1996 Mar, 14(5), 641 - 54 High-pressure liquid chromatographic methods for ciprofloxacin hydrochloride and related compounds in raw materials; Lacroix PM et al.; High-pressure liquid chromatographic (HPLC) methods were developed for the analysis of ciprofloxacin hydrochloride raw materials . Method A is for drug content and the determination of related compounds eluting before the drug, including the ethylenediamine analog of ciprofloxacin . Method B may be used for the determination of fluoroquinolonic acid and other related compounds eluting after the drug . Both methods require a 5 microns Inertsil ODS2 column (150 x 4.6 mm), a mobile phase containing tetrahydrofuran, acetonitrile and buffer (0.005 M 1-hexane-sulphonic acid sodium adjusted to pH 3.0 with 0.1 M phosphoric acid); 10:5:85 (v/v/v) for method A and 25:15:60 (v/v/v) for method B, and a flow rate of 1 ml min-1 . Detection for method A is at 254 nm; a programmable variable wavelength detector is required for method B: 254 nm for 12 min, then 220 nm for 23 min . The limit of quantitation of the related compounds was 0.05% or less . The precision of the assay method was lower than 1.0% . Drug content in four raw material samples ranged from 98.7% to 101.6% calculated with reference to the anhydrous substance . The water content in these samples ranged from 5.9% to 7.8% . Total impurity levels were 1.0% or lower . Levels of ethylenediamine analog and fluoroquinolonic acid were below 0.4% . A second analyst, using a different HPLC system and a column from a different supplier, repeated the analysis of two raw materials samples and obtained similar results. Invest Ophthalmol Vis Sci, 1996 Mar, 37(4), 656 - 65 In vitro effects of aminoglycosides and fluoroquinolones on keratocytes; Seitz B et al.; PURPOSE: Commonly used fluoroquinolones are reported to have less of an effect than aminoglycosides on corneal epithelial cells . The purpose of this study was to assess the effects of these antibiotics on stromal keratocytes in vitro . METHODS: Cultured rabbit keratocytes were incubated with various concentrations of gentamicin, tobramycin, ofloxacin, norfloxacin, and ciprofloxacin . Evaluations were performed by means of phase-contrast microscopy and {3H}thymidine uptake assay after 24 hours and 48 hours of incubation with the drug (concentrations from 3 to 0.003 mg/ml) . RESULTS: At a concentration of 3 mg/ml, all three fluoroquinolones inhibited keratocyte proliferation significantly more than either aminoglycoside after 24 hours (P<0.001) and after 48 hours (P<0.001) . In contrast to the aminoglycosides, all three fluoroquinolones induced a dose- dependent inhibition of proliferation after 24 hours . Even at the lowest concentration (0.003 mg/ml), ofloxacin and norfloxacin inhibited keratocyte proliferation significantly (P=0.001) compared to control after 24 hours . Concentrations of fluoroquinolones ranging from 0.09 to 0.24 mg/ml produced a 50% inhibition of proliferation, a level of inhibition not observed with any tested concentration of aminoglycosides . After 24 hours, all three fluoroquinolones, but neither of the aminoglycosides, showed moderate to severe signs of cytotoxicity at a concentration of 3 mg/ml . CONCLUSIONS: Relative effects of fluoroquinolones and aminoglycosides on epithelial cells and stromal keratocytes appear to be different . This might have an impact on choosing the optimal antibiotic drug to be applied prophylactically in clinical situations in which the epithelium is absent, such as after photorefractive keratectomy or chemical burn. Clin Infect Dis, 1996 Feb, 22(2), 251 - 6 Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin; Israel DS et al.; To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period . Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks . By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020) . The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy . We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin. Antimicrob Agents Chemother, 1996 Feb, 40(2), 491 - 3 Detection of mutations in parC in quinolone-resistant clinical isolates of Escherichia coli; Vila J et al.; The gene parC encodes the A subunit of topoisomerase IV of Escherichia coli . Mutations in the parC region analogous to those in the quinolone resistance-determining region of gyrA were investigated in 27 clinical isolates of E . coli for which ciprofloxacin MICs were 0.0007 to 128 micrograms/ml . Of 15 isolates for which ciprofloxacin MICs were > or = 1 microgram/ml, 8 showed a change in the serine residue at position 80 (Ser-80), 4 showed a change in Glu-84, and 3 showed changes in both amino acids . No mutations were detected in 12 clinical isolates for which ciprofloxacin MICs were < or = 0.25 micrograms/ml . These findings suggest that ParC from E . coli may be another target for quinolones and that mutations at residues Ser-80 and Glu-84 may contribute to decreased fluoroquinolone susceptibility. J Pediatr Hematol Oncol, 1996 Feb, 18(1), 63 - 7 Fractionated high-dose cyclophosphamide for advanced pediatric solid tumors; Chan LL et al.; PURPOSE: The objective of this study was to determine the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/m2 given in four fractions over 8 h in children with advanced solid tumors . PATIENTS AND METHODS: Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of high-dose CPA at 7 g/m2 for the treatment of advanced malignant solid tumor . CPA was given in four 1-h infusions of 1.75 g/m2 each, with 1 h of rest between each dose . MESNA was used as a uroprotective agent and was continued for 24 h after the final dose of CPA . With only one exception, all patients were discharged at the end of MESNA infusion and received granulocyte colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole . RESULTS: Severe but transient myelosuppression was observed . The median time to neutrophil and platelet recovery was 17 and 19 days, respectively . Fever developed after 13 of the 24 courses, and hospitalization was required . Extramedullary toxicities were mild . No patient showed cardiomyopathy or hemorrhagic cystitis . Forty-six percent of the courses were managed entirely on an outpatient basis . Objective tumor response was seen in five patients . CONCLUSIONS: CPA at 7 g/m2 is well tolerated by children with advanced malignancies and should be considered in earlier phases of antineoplastic therapy. Lancet, 1996 Jan 27, 347(8996), 233 - 5 Comparison of 99mTc infecton imaging with radiolabelled white-cell imaging in the evaluation of bacterial infection; Vinjamuri S et al.; BACKGROUND: Bacterial infection can pose a substantial diagnostic dilemma . Techniques involving radiolabelled leucocytes can pinpoint the site of inflammation . However, previous radiolabelling techniques have failed to distinguish between bacterial-mediated infection and non-bacterial inflammation . To overcome this difficulty, we have studied a radiopharmaceutical, technetium-99m (99mTc) Infecton, which is based on the antibiotic ciprofloxacin . METHODS: We used this agent to image bacterial infection in 56 patients (one twice) with known or suspected sites of infection . We then compared the imaging results of these patients with those from a radiolabelled leucocyte study . FINDINGS: The concordance rate was 68% (39 out of 57 images) . In 18 discordant results 99mTc Infecton was correctly positive in 8 out of 9 positive studies and correctly negative in 4 out of 9 negative studies . 4 out of 5 of the falsely negative studies were in patients who had taken antibiotics for over 7 days . We found that 99mTc Infecton gave better imaging results than radiolabelled leucocytes . Comparison between 99mTc Infecton and leucocyte imaging gave sensitivities of 84% and 81%, and specificities of 96% and 77%, respectively . INTERPRETATION: We believe that the specificity 99mTc Infecton confers for bacterial infection and its ease of administration are the main advantages of this new agent. J Chromatogr B Biomed Appl, 1996 Jan 26, 675(2), 243 - 50 Simultaneous determination of danofloxacin and N-desmethyldanofloxacin in cattle and chicken edible tissues by liquid chromatography with fluorescence detection; Strelevitz TJ et al.; A rugged, simple, and selective method for the determination of danofloxacin and its primary metabolite, N-desmethyldanofloxacin, in cattle (liver, muscle, kidney, and fat) and chicken (liver and muscle) tissues was developed . The method is selective for danofloxacin and N-desmethyldanofloxacin over other veterinary important fluoroquinolones, such as enrofloxacin, ciprofloxacin, norfloxacin, and ofloxacin . Selectivity is achieved through a combination of extraction, chromatography, and fluorescence detection . The analytes were extracted from homogenized tissues using a methanol-perchloric-phosphoric acid solution . After centrifugation, direct injection of extraction supernate was possible . The limit of quantitation was 20 pg on column . Separation was achieved on an Inertsil C8 (5 microns, 100 A) column with dimensions of 250 x 4.6 mm I.D . The mobile phase consisted of 0.05 M phosphate buffer (pH 3.5)-acetonitrile (88:12) . A fluorescence detector was utilized with an excitation wavelength of 280 nm and an emission wavelength of 440 nm . The assay was accurate and reproducible within the range of 10 to 500 ng/g for both danofloxacin and N-desmethyldanofloxacin . Intra-assay accuracy was between 98 and 101%, and precision was less than 4% . Inter-assay accuracy was between 99 and 102%, while precision was less than 2% . Recoveries for both analytes over the dynamic range were greater than 90% for all the tissues. Tsitologiia, 1996, 38(9), 958 - 73 {The genotoxic effect of ciprofloxacin on cultured cells from the kangaroo rat kidney and on skin fibroblasts from the Indian muntjac}; Polianskaia GG et al.; The genotoxicity of an antibiotic ciprofloxacin (CF) in doses of 10, 25, 50 and 100 mkg/ml under its short-term (6-48 h) and long-term (15-30 days) action on sublines of Rat kangaroo kidney, NBL-3-11, and Indian muntjak skin fibroblasts has been studied . The emergence of genotoxic effect depends on the dose and time of ciprofloxacin action on both the sublines, but the degree of this effect does not depend on these parameters directly . Ciprofloxacin exerts no influence on cell distribution for chromosome number in subline NBL-3-11, and increases heterogeneity of this parameter in the subline of Indian muntjac skin fibroblasts in 30 days after its addition in doses of 25 and 50 mkg/ml . The degree of increase of chromosomal aberrations in the subline of Indian muntjak skin fibroblasts was in average 1.5 times more than in NBL-3-11 in all examined variants compared to the control . The minimum antibiotic dose that induced chromosomal aberrations was 25 mkg/ml in the subline of NBL-3-11 under a short-term action and 50 mkg/ml under a long-term action . For the subline of Indian muntjac skin fibroblasts the minimum inducing dose was 50 mkg/ml irrespective of the duration of action, except the case of 15 days, when the number of dicentrics increased still at 25 mkg/ml . In both sublines with the duration of ciprofloxacin action within 6-24 h the replacement of chromatid aberrations by chromosomal aberrations occurred . Under a long-term ciprofloxan action differences in types of chromosomal aberrations were discovered: for subline NBL-3-11 these were mainly chromosomal breaks; in the case of muntjac cells both chromosomal breaks and dicentrics (telomeric associations) occurred . The preferential involvement of some chromosomes in dicentric formation was observed . In cells of the muntjac subline, unlike NBL-3-11, the sensitivity of individual chromosomes to ciprofloxacin-induced breaks differed from that to spontaneous breaks . In both the sublines ciprofloxacin induces chromosomal breaks mainly in definite regions of chromosomes . Possible reasons of differences between the examined sublines towards the character of chromosomal instability are discussed in addition to the role of dicentrics as a proposed adaptation of cells to unfavourable factors of the environment. Ophthalmologica, 1996, 210(2), 119 - 22 Absorption of topically administered ciprofloxacin, ofloxacin and gentamicin in the inflamed rabbit eye; Behrens-Baumann W; The authors evaluated the ocular absorption of ciprofloxacin, ofloxacin and gentamicin as a reference drug in a novel model of ocular inflammation . The ocular absorption of ciprofloxacin and ofloxacin was shown to be increased two- to threefold in the inflamed eye . The absorption of gentamicin was undetectable in the normal eye and very poor in the inflamed eye. J Pharm Biomed Anal, 1996 Jan, 14(3), 353 - 6 Rapid liquid chromatographic assay of ciprofloxacin in human aqueous humor; Basci NE et al.; A simple, selective and sensitive method has been developed to determine ciprofloxacin in human aqueous humor . Separation of ciprofloxacin was carried out with pipemidic acid as internal standard using a Novapak C18 reversed-phase cartridge column (100 x 8 mm i.d., particle size 4 microns) and a mobile phase consisting of methanol-acetonitrile-citric acid (0.4 M) (3:1:10, v/v/v) at a flow rate of 1 ml min-1 . The column effluent was monitored with fluorescence detection at 278 nm (excitation) and 450 nm (emission) after direct injection . The retention times were 4.88 min for pipemidic acid and 7.52 min for ciprofloxacin . The within-day and day-to-day reproducibilities were less than 7% for ciprofloxacin at 0.1 and 1 microgram ml-1 (n = 6) . The mean recovery from aqueous humor was found to be 101.37 +/- 6.7% for ciprofloxacin at 0.1 micrograms ml-1 (n = 6 and the detection limit corresponding to a signal-to-noise ratio of 2.5:1 was 250 pg ml-1 . The method was shown to be suitable for determining ciprofloxacin levels in human aqueous humor samples. Antimicrob Agents Chemother, 1996 Jan, 40(1), 11 - 3 Excretion of ciprofloxacin into the large bowel of the rabbit; Ramon J et al.; The intestinal elimination of ciprofloxacin in the large bowel was studied in a rabbit model . Segments from the cecum, colon, and sigmoid colon along with their intact blood vessels were isolated and perfused, and their contents were collected over a 90-min period following the administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight . The elimination rates of ciprofloxacin were 0.126 +/- 0.084 micrograms.min-1.cm-2 in the cecum and 0.264 +/- 0.126, 0.11 +/- 0.07, and 0.21 +/- 0.141 micrograms.min-1.cm-2 in the proximal colon, distal colon, and sigmoid colon, respectively . The calculated fraction of ciprofloxacin eliminated in the large bowel was 3% of the parenteral dose administered . The elimination pattern of ciprofloxacin in the large bowel may explain the unusual activity of this fluoroquinolone in modifying the colonic flora. Antimicrob Agents Chemother, 1996 Jan, 40(1), 6 - 10 Ciprofloxacin absorption is impaired in patients given enteral feedings orally and via gastrostomy and jejunostomy tubes; Healy DP et al.; Twenty-six hospitalized patients participated in a randomized crossover study to evaluate the effect of enteral feedings on ciprofloxacin absorption when given orally or via gastrostomy or jejunostomy tubes . Patients in the oral group received an intact 500-mg ciprofloxacin tablet alone or ciprofloxacin plus three oral doses of Sustacal (240 ml given 8 h before, with, and 4 h after ciprofloxacin administration) . Patients with gastrostomy or jejunostomy tubes received 500 mg of crushed ciprofloxacin in 60 ml water via the feeding tube . After a washout period, the patients received ciprofloxacin with a continuous enteral formula (Jevity) given at 60 to 90 ml/h beginning 6 h before drug administration and continuing for 10 h . Serial blood samples were analyzed for ciprofloxacin concentration by high-performance liquid chromatography . The maximum ciprofloxacin concentrations in serum for ciprofloxacin given and for ciprofloxacin plus enteral feeding for the oral, gastrostomy, and jejunostomy groups were (mean +/- standard deviation) 2.59 +/- 1.24 versus 1.43 +/- 0.61 micrograms/ml (P < 0.05), 3.68 +/- 1.36 versus 2.27 +/- 0.67 micrograms/ml (P < 0.05), and 3.78 +/- 1.87 versus 1.45 +/- 0.48 micrograms/ml (P < 0.05), respectively . Corresponding values for area under the concentration-time curve were 13.4 +/- 8.32 versus 9.44 +/- 4.74 micrograms/h/ml (P < 0.05) 15.9 +/- 6.62 versus 7.44 +/- 3.16 (micrograms/h/ml (P < 0.05), and 18.1 +/- 9.37 versus 5.82 +/- 2.63 micrograms.h/ml (P < 0.05) . We conclude that enteral feedings given orally or via gastrostomy or jejunostomy tubes resulted in a 27 to 67% reduction in the mean bioavailability of ciprofloxacin in hospitalized patients . The decreased absorption may be clinically important, especially when the enteral feeding is coadministered with ciprofloxacin by the oral and jejunostomy tube routes . Reductions in maximum levels of ciprofloxacin in serum as a result of feedings given via a gastrostomy tube are similar to those following oral administration on an empty stomach, making a clinically important interaction by this route less likely. J Ocul Pharmacol Ther, 1996 Summer, 12(2), 183 - 91 Intravitreal delivery of ciprofloxacin; Hainsworth DP et al.; The objective of this work was to evaluate various methods of sustained delivery to achieve therapeutic intravitreal levels of ciprofloxacin as a potential therapy for endophthalmitis . Two types of intravitreal bioerodible sustained release devices of ciprofloxacin were evaluated in vitro . The most promising device was evaluated in rabbits and results compared with subconjunctival injections of a ciprofloxacin suspension . Subconjunctival injections failed to deliver therapeutic concentrations of ciprofloxacin into either the aqueous or vitreous . In vivo evaluation of the intravitreal device consistently delivered ciprofloxacin at levels above 1 ug/ml for up to four weeks . No retinal activity was noted by clinical examination or by electroretinogram . Intravitreal implantation of bioerodible ciprofloxacin devices can maintain vitreous concentrations above 1 ug/ml, more than the MIC90 of most organisms associated with endophthalmitis . Implantation of these devices appears to be well tolerated and may represent a viable treatment for this disease . Further studies in endophthalmitis models are needed to evaluate device efficacy. Br J Dermatol, 1996 Jan, 134(1), 156 - 8 Fixed drug eruption due to ciprofloxacin; Dhar S et al.; We describe seven patients with fixed drug eruption (FDE) due to ciprofloxacin, five confirmed by rechallenge . These cases make up 8.75% of all cases of FDE seen by us during 1992-93 . Isolated, and striking involvement of the lips was seen in two patients . To our knowledge, only a single case of FDE to ciprofloxacin previously has been reported . Our experience suggests that, with widespread use, ciprofloxacin could become one of the common drugs causing FDE. Ophthalmic Surg Lasers, 1996 Jan, 27(1), 21 - 4 Penetration of topical 0.3% ciprofloxacin into human aqueous humor; Kalayci D et al.; BACKGROUND AND OBJECTIVE: Investigation of the penetration of topical ciprofloxacin into aqueous humor . PATIENTS AND METHODS: Topical 0.3% ciprofloxacin drops were administered to 17 patients with cataracts before lens extraction surgery . The time interval between the first dose and sampling was 3 hours in 9 patients (group A) and 6 hours in 8 (group B) . In both groups, aqueous samples were collected 30 minutes after the last ciprofloxacin application . Ciprofloxacin concentration was determined by high-performance liquid chromatography-fluorescence detection . RESULTS: Mean aqueous concentration was 0.83+/-0.48 microgram/ml in group A and 2.42+/-1.42 micrograms/ml in group B . CONCLUSION: Topical 0.3% ciprofloxacin penetrates into the aqueous in a significant concentration. Harefuah, 1995 Dec 1, 129(11), 470 - 2, 535 {Ciprofloxacin-associated bilateral acute achilles tendinitis}; Mirovsky Y et al.; Bilateral achilles tendinitis developed in a 40-year-old man following treatment with Ciprofloxacin, 500 mg twice a day, for prostatis . The signs of tendinitis resolved 6 weeks after cessation of the drug . In recent years very few cases of this rare complication have been reported . In some cases it results in a torn achilles tendon . If diagnosed early, complete recovery usually follows about 6 weeks after cessation of the drug. Zentralbl Veterinarmed A, 1995 Dec, 42(10), 669 - 73 Compositional analysis surveillance of eleven brands of enrofloxacin including Baytril for veterinary use; Sumano H et al.; Lack of consistency in clinical effectiveness of various commercial preparations of enrofloxacin prompted a compositional analysis surveillance of 11 trade marks of this fluoroquinolone using various physicochemical properties and high performance liquid chromatography (HPLC) . Only one preparation resembled Baytril (Bayer of Mexico), the original brand of enrofloxacin . Variations in the concentration of enrofloxacin, use of different vehicles, substitution of this fluoroquinolone by ciprofloxacin and variations in pH were found . The use of ciprofloxacin in veterinary medicine is discussed. Neuropharmacology, 1995 Dec, 34(12), 1615 - 24 A patch clamp study of the effects of ciprofloxacin and biphenyl acetic acid on rat hippocampal neurone GABAA and ionotropic glutamate receptors; Halliwell RF et al.; The neurotoxic effects of 4-quinolones alone and in combination with certain non-steroidal anti-inflammatory drugs (NSAIDs) may be related to an interaction at GABAA and/or ionotropic glutamate receptors . In the present study, the effects of the fluoroquinolone, ciprofloxacin, alone and in combination with the NSAID, biphenyl acetic acid (BPAA), were examined on GABAA-, NMDA-, AMPA-, and kainate-evoked current responses recorded from cultured rat hippocampal neurones, using the whole cell patch clamp technique . GABA-evoked currents were reversibly inhibited by bicuculline (3 microM) and ciprofloxacin (100 microM) to 11 +/- 5 and 38 +/- 7% of control, respectively . BPAA (100 microM) had little affect on the GABA current (the response was 82 +/- 4% of control) but enhanced the inhibitory potency of ciprofloxacin by approx . 3000-fold . The antagonist effects of ciprofloxacin (30 microM) and ciprofloxacin (0.03 microM) together with BPAA (100 microM) on the GABA-evoked current were not voltage-dependent . Whole cell currents evoked by NMDA, AMPA or kainate were little influenced by ciprofloxacin (100 microM), BPAA (100 microM), or ciprofloxacin plus BPAA (both at 100 microM); the responses being > or = 90% of control in all cases . These data suggest that the proconvulsant effects of quinolones when combined with BPAA may be related to antagonism of central GABAA receptors but not to an interaction at ionotropic glutamate receptors. Arch Biochem Biophys, 1995 Dec 1, 324(1), 123 - 9 Mycobacterial DNA gyrase: enzyme purification and characterization of supercoiling activity; Wu LC et al.; Putative structural genes encoding Mycobacterium bovis BCG gyrase A and gyrase B subunits were expressed in Escherichia coli under the control of a regulated promoter . Upon induction, high levels of proteins of M(r) 92,000 and 75,000 were generated . Purification and reconstitution of these proteins yielded an enzyme with bacterial DNA gyrase activity . DNA supercoiling activity of the mycobacterial enzyme required ATP, Mg2+, and spermidine . Like other bacterial DNA gyrases, the supercoiling activity of the mycobacterial enzyme was inhibited by low concentration of the classical gyrase B subunit inhibitors novobiocin and coumermycin . Older gyrase A subunit inhibitors, nalidixic and oxolinic acid, had no effect on the supercoiling activity at 400 to 800 micrograms/ml . However, in vitro assays to show the inhibition of supercoiling activity and stimulation of cleavable complex formation demonstrated that ciprofloxacin is a potent inhibitor of mycobacterial DNA gyrase . The availability of highly purified mycobacterial DNA gyrase could aid in future investigations of quinolone derivatives targeting Mycobacterium specifically. Hepatology, 1995 Dec, 22(6), 1797 - 800 Ciprofloxacin prevents the inhibitory effects of acute ethanol exposure on hepatic regeneration in the rat; Minuk GY et al.; To determine whether the inhibitory effects of ethanol on hepatic regeneration could be prevented by ciprofloxacin, a fluroquinolone antibiotic with gamma-aminobutyric acid (GABAA), receptor antagonist properties, adult, male Sprague-Dawley rats (n = 6-8/group) received intraperitoneal injections of saline, putrescine (a hepatic growth promoter, 50 mg/kg), or ciprofloxacin (100 mg/kg), followed 1 hour later by gastric gavage with saline or ethanol (5 g/kg) . One hour post-gavage, all rats underwent a 70% partial hepatectomy (PHx) . Hepatic regenerative activity was documented 24 hours post-PHx by 3H-thymidine incorporation into hepatic DNA (DNA synthesis), proliferating cell nuclear antigen staining, and hepatic tissue putrescine levels . Compared with healthy controls, DNA synthesis rates were significantly lower in ethanol-gavaged/saline-treated rats (22.7 +/- 4.4 x 10(3) vs . 12.3 +/- 6.9 x 10(3) DPM/mg DNA, respectively, P < .001) but unaltered in putrescine-(18.8 +/- 3.4 x 10(3) DPM/mg DNA) and ciprofloxacin-treated (18.3 +/- 2.6 x 10(3) DPM/mg DNA) rats . Hepatic proliferating cell nuclear antigen staining supported these findings . Hepatic putrescine levels also correlated with DNA synthesis data, being decreased in ethanol-gavaged/saline-treated rats (86 +/- 14 pmoles/mg tissue) compared with healthy controls (120 +/- 12 pmoles/mg, P < .01), ethanol-gavaged/putrescine-treated (112 +/- 14 pmoles/mg, P < .05) and ethanol-gavaged/ciprofloxacin-treated (125 +/- 17 pmoles/mg, P < .05) rats . To determine whether these effects resulted from GABAA receptor-mediated changes in liver membrane potentials, intracellular membrane potentials were recorded before and 1 hour after PHx in healthy control, ethanol-gavaged/saline-treated and ethanol-gavaged/ciprofloxacin-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS) Indian J Exp Biol, 1995 Nov, 33(11), 883 - 5 Protective effect of fluoroquinolones on dapsone induced erythrolysis; Chatterjee N et al.; Various quinolones have varied effects on the preservative activity of blood cells . Nalidixic acid causes hemolysis in G-6PD deficient patients where as ofloxacin has been found to possess preservative action of WBCs . The present study was undertaken to see the effect of various fluoroquinolones on RBC membrane . The effect of quinolones like ciprofloxacin, ofloxacin and norfloxacin and nalidixic acid in the dose of 5 micrograms/ml was studied on dapsone induced, in vitro hemolysis of rabbit RBC, using the osmotic fragility test . The mean corpusular fragility (MCF) with various agents were as follows: (mean +/- SE) saline; 5.23 +/- 0.21; dapsone, 6.57 +/- 0.23; ofloxacin, 3.81 +/- 0.13; ofloxacin and dapsone, 5.13 +/- 0.11; nalidixic acid, 6.28 +/- 0.16; nalidixic acid and dapsone, 6.65 +/- 0.13; ciprofloxacin, 3.52 +/- 0.22; ciprofloxacin and dapsone, 4.80 +/- 0.2; norfloxacin, 1.97 +/- 0.23; norfloxacin and dapsone, 4.27 +/- 0.20 . The MCF data and shift of the osmotic fragility curves (to the left) show that dapsone induced erythrolysis is significantly protected by ciprofloxacin, ofloxacin and norfloxacin but not by nalidixic acid. Biochim Biophys Acta, 1995 Nov 1, 1239(2), 145 - 56 Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery; Lasic DD et al.; Phase transitions in closed vesicles, i.e., microenvironments defined by the size of the vesicle, its contents, and permeability of its membrane are becoming increasingly important in several scientific disciplines including catalysis, growth of small crystals, cell function studies, and drug delivery . The membrane composed from lipid bilayer is in general impermeable to ions and larger hydrophilic ions . Ion transport can be regulated by ionophores while permeation of neutral and weakly hydrophobic molecules can be controlled by concentration gradients . Some weak acids or bases, however, can be transported through the membrane due to various gradients, such as electrical, ionic (pH) or specific salt (chemical potential) gradients . Upon permeation of appropriate species and reaction with the encapsulated species precipitation may occur in the vesicle interior . Alternatively, these molecules can also associate with the leaflets of the bilayer according to the transmembrane potential . Efficient liposomal therapeutics require high drug to lipid ratios and drug molecules should have, especially when associated with long circulating liposomes, low leakage rates . In this article we present very efficient encapsulation of two drugs via their intraliposomal precipitation, characterize the state of encapsulated drug within the liposome and try to fit the experimental data with a recently developed theoretical model . Nice agreement between a model which is based on chemical potential equilibration of membrane permeable species with experimental data was observed . The high loading efficiencies, however are only necessary but not sufficient condition for effective therapies . If adequate drug retention within liposomes, especially in the case of long-circulating ones, is not achieved, the therapeutic index decreases substantially . Anticancer drug doxorubicin precipitates in the liposome interior in a form of gel with low solubility product and practically does not leak out in blood circulation in the scale of days . With an antibiotic, ciprofloxacin, the high loading efficacy and test tube stability is not reproduced in in vitro plasma leakage assays and in vivo . We believe that the reasons are higher solubility product of precipitated drug in the liposome, larger fraction of neutral molecules due closer pK values of the drug with the pH conditions in the solutions and high membrane permeability of this molecule . High resolution cryoEM shows that encapsulated anticancer agent doxorubicin is precipitated in the form of bundles of parallel fibers while antibiotic ciprofloxacin shows globular precipitate . Doxorubicin gelatin also causes the change of vesicle shape. Biochem Pharmacol, 1995 Oct 26, 50(9), 1517 - 20 Enoxacin is an inducer of CYP1A2 in rat liver; Schulz TG et al.; The induction of cytochrome P450 by enoxacin, ciprofloxacin, and ofloxacin was investigated in female Wistar rats . Animals were treated orally with daily doses ranging from 10 to 400 mg enoxacin per kg body wt, 400 mg ciprofloxacin, or 400 mg ofloxacin per kg body wt for up to 7 days . Activities of methoxyresorufin O-demethylase (MROD) and ethoxyresorufin O-deethylase (EROD) were determined fluorimetrically in hepatic microsomes . MROD activity was increased 2.6-fold after treatment with 100 mg enoxacin per kg body wt for 7 days . Lower doses of enoxacin did not induce MROD activity significantly . Antipeptide antibodies directed specifically against different rat cytochrome P450 enzymes demonstrated that CYP1A2, but not CYP1A1, was induced in rats treated with enoxacin . After ciprofloxacin or ofloxacin treatment, no induction of MROD or EROD activity was observed . Neither ciprofloxacin nor ofloxacin caused any change in CYP1A1 or CYP1A2 apoprotein levels . Further investigations with antipeptide antibodies showed that there was no induction of CYP2B1, CYP2B2, CYP2E1, CYP3A1, CYP3A2, CYP4A1, or CYP4A2 following treatment with enoxacin, ciprofloxacin, or ofloxacin . It is concluded that enoxacin, but not ciprofloxacin or ofloxacin, is an inducer of CYP1A2 in rat liver. Antimicrob Agents Chemother, 1995 Oct, 39(10), 2316 - 9 Treatment of Mycobacterium haemophilum infection in a murine model with clarithromycin, rifabutin, and ciprofloxacin; Atkinson BA et al.; An animal model of disseminated Mycobacterium haemophilum infection was utilized to compare treatment with azithromycin, ciprofloxacin, rifabutin, and the combination of clarithromycin with rifabutin . Following subcutaneous challenge with M . haemophilum, local and disseminated infection occurred only in immunosuppressed mice . For disseminated infection, ciprofloxacin was relatively ineffective therapy . Clarithromycin and rifabutin alone significantly reduced the tissue burden in the spleen after 4 weeks of therapy . Combination therapy with rifabutin and clarithromycin was superior to 4 weeks of treatment with the individual agents . When immunosuppressed mice were treated for 20 weeks with the combination of rifabutin and clarithromycin, the tissue burden remained reduced in the spleen at 1 month following the completion of therapy . Combined rifabutin and clarithromycin provide effective treatment for M . haemophilum in this model. J Biomater Appl, 1995 Oct, 10(2), 163 - 70 Controlled release of newer quinolones from biodegradable systems based on poly(lactic acid); Andreopoulos AG; The release of newer quinolones (such as pefloxacin, ofloxacin, and ciprofloxacin) from biodegradable poly(D, L lactic acid) has been investigated . The in vitro study showed that drug delivery takes place for about two months and a maximum in concentration was recorded after fifteen days . The release from poly(lactic acid) slabs seemed to give high drug doses that are adequate for the treatment of infections caused by common pathogens. J Antimicrob Chemother, 1995 Oct, 36(4), 717 - 21 Enteric absorption of ciprofloxacin during the immediate postoperative period; Cohn SM et al.; We studied the enteric absorption of ciprofloxacin immediately following major abdominal surgery to determine if this drug could replace parenteral agents . Nine critically ill subjects received ciprofloxacin, 750 mg, every 12 h for 48 h via nasogastric tube . Drug concentrations were measured after the first and fourth doses . There was insignificant absorption after the initial dose, Cmax = 0.6 +/- 0.6 (mg/L) and AUC0-12 = 3.5 +/- 3.2 (mg.h/L) . Unfortunately, serum ciprofloxacin concentrations were also minimally detectable in three of nine subjects after the fourth dose . Enteric absorption of ciprofloxacin, therefore, was erratic and unpredictable in critically ill patients following major abdominal surgery. Eur J Vasc Endovasc Surg, 1995 Oct, 10(3), 346 - 51 Oral ciprofloxacin versus intravenous cefuroxime as prophylaxis against postoperative infection in vascular surgery: a randomised double-blind, prospective multicentre study; Risberg B et al.; OBJECTIVES: To test the hypothesis that oral ciprofloxacin is equally effective as intravenous cefuroxime in preventing postoperative infectious complications in patients undergoing peripheral arterial surgery involving the groins . DESIGN: Prospective, randomised, double-blind multicentre study . MATERIALS: 580 patients undergoing arterial surgery involving the groins were randomised to ciprofloxacin (Ciproxin, Bayer) 750 mg x 2 p.o . or cefuroxime (Zinacef, Glaxo) 1.5 g x 3 i.v . given only on the day of surgery . The primary endpoint was wound/graft infection within 30 days postoperatively . Wound infection was defined as pus . RESULTS: The wound infection rate in the ciprofloxacin group was 9.2% (27 patients) and in the cefuroxime group 9.1% (26 patients) according to intention to treat . For correct treatment the corresponding numbers were 9.5% (23 patients) and 9.7% (22 patients), respectively . There were three graft infections (0.5%) . The infection rate was 7.1% (31/433) in the absence and 14.9% (22/147) in the presence of distal ulcers (p < 0.05) . S . allreus was the most common bacteria isolated . Forty percent of the wound infections were localised to the groins . By multivariate analysis presence of distal ulcer was the only factor of prognostic significance . CONCLUSIONS: The infection rate was similar in the two groups . Thus, oral administration of ciprofloxacin is an attractive, cost-effective and safe alternative to prophylaxis in vascular patients capable of taking oral medication on the day of surgery. Gastroenterol Clin North Am, 1995 Sep, 24(3), 509 - 21 Conventional drug therapy in inflammatory bowel disease; Griffin MG et al.; The conventional treatment of inflammatory bowel disease should center around the liberal use of one of the many available forms of 5-ASA . Sulfasalazine should be used initially with the newer mesalamine-only containing drugs being reserved for sulfasalazine-intolerant patients or for those patients who require larger doses of medication . The choice of the delivery method should be made with the knowledge of the extent of disease and the potential coverage areas of the individual delivery methods . Systemic and topical glucocorticoids are an invaluable adjunct to 5-ASA therapy, but their use must be directed with the goal of remission induction . The tapering of glucocorticoids should be as prompt as the maintenance of remission allows, with a useful general guideline of decreasing the dose by 1 mg per day . Immunosuppressive therapy, including azathioprine and 6-mercaptopurine, holds promise for refractory cases of inflammatory bowel disease and for their potential steroid sparing properties; antibiotic therapy with metronidazole and ciprofloxacin in the absence of documented infectious disease offers additional routes to control disease . The majority of patients require a combination of drugs to attain remission . Only further study will reveal the ideal regimen for each of the different subsets of inflammatory bowel disease. Pharm Res, 1995 Sep, 12(9), 1299 - 303 The intestinal transport mechanism of fluoroquinolones: inhibitory effect of ciprofloxacin, an enoxacin derivative, on the membrane potential-dependent uptake of enoxacin; Hirano T et al.; PURPOSE . To clarify the absorption-structure relationship for the fluoroquinolones from the point of view of inhibitory behavior . METHODS . The inhibitory effects of ciprofloxacin on the transport process of enoxacin across the rat intestinal brush-border membrane was examined . RESULTS . Ciprofloxacin, which has a similar structure to enoxacin, exhibited a pH-dependent interference with enoxacin absorption from rat jejunal loops . The uptake experiments using BBM vesicles showed that ciprofloxacin significantly reduced not only the initial binding of enoxacin to the membrane surface, but also the K(+)- or H(+)-diffusion potential-dependent transport across the membrane . Furthermore, an H(+)-diffusion potential (interior negative) also exhibited a stimulative uptake of ciprofloxacin . CONCLUSIONS . These results suggest that the inhibition behavior of ciprofloxacin from the jejunal loop was closely related to the ionic diffusion potential-dependent uptake of enoxacin across the brush-border membrane. Infection, 1995 Sep-Oct, 23(5), 278 - 82 Ciprofloxacin vs . cefotaxime regimens for the treatment of intra-abdominal infections; Hoogkamp-Korstanje JA; The efficacy of ciprofloxacin plus metronidazole was compared with that of cefotaxime plus gentamicin plus metronidazole in 79 patients with proven intra-abdominal infections . Patients were classified with the Peritonitis Index Altona-II (PIA-II) score for severity of disease, underlying conditions, prognosis and type of infection . Local peritonitis was diagnosed in 21 patients, generalized peritonitis in 25, intra-abdominal abscesses in 33; 35 patients had polymicrobial infections . Cure and improvement rates were: ciprofloxacin 77%, cefotaxime combination 56% (p < 0.02) . Failures were significantly associated with a low initial PIA-II score, the presence of generalized peritonitis or abscesses, persistence of pathogens and superinfection . Superinfection was observed in 49% of the cases under cefotaxime and in 30% under ciprofloxacin . Concentrations of ciprofloxacin in pus ranged 2.0-5.2 mg/l with simultaneous serum concentrations of 1.2-3.1 mg/l. Antimicrob Agents Chemother, 1995 Sep, 39(9), 2161 - 3 Absorption of ciprofloxacin in patients with diabetic gastroparesis; Marangos MN et al.; The purpose of this study was to assess the pharmacokinetic profile of ciprofloxacin in 12 patients with diabetic gastroparesis . Patients received both a single 500-mg oral (p.o.) dose and a single 400-mg intravenous (i.v.) dose of ciprofloxacin separated by a 1-week washout period . Pharmacokinetic parameters (means +/- standard deviations) for the p.o . and i.v . doses were as follows: areas under the concentration-time curve from 0 h to infinity, 9.74 +/- 2.59 and 11.78 +/- 3.18 micrograms.h/ml, respectively; maximum concentrations of drug in serum, 2.13 +/- 0.67 and 4.21 +/- 1.07 micrograms/ml, respectively; and half-lives, 4.03 +/- 0.58 and 4.20 +/- 0.58 h, respectively . The ratio of the areas under the concentration-time curves from 0 h to infinity for the p.o . and i.v . doses was 0.84, with a 90% confidence interval of 0.68 to 0.98; the mean absolute bioavailability was calculated to be 67% (range, 43 to 82%) . From these data it appears that ciprofloxacin is adequately absorbed in patients with diabetic gastroparesis. Am J Kidney Dis, 1995 Sep, 26(3), 516 - 9 Renal vasculitis associated with ciprofloxacin; Shih DJ et al.; We report two patients treated with ciprofloxacin who presented with acute renal failure . On renal biopsy, a necrotizing vasculitis was identified in addition to acute interstitial nephritis . Improvement in renal function resulted with the discontinuation of the antibiotic and the institution of immunosuppressive therapy. J Antimicrob Chemother, 1995 Aug, 36(2), 431 - 4 Cross-resistance analysis for clinafloxacin compared with ciprofloxacin, fleroxacin, ofloxacin, and sparfloxacin using a predictor panel of ciprofloxacin-resistant bacteria; Cormican MG et al.; Clinafloxacin was significantly more active against fluoroquinolone-resistant organisms than ciprofloxacin, ofloxacin, sparfloxacin and fleroxacin . Clinafloxacin inhibited 65% of isolates at the recommended breakpoint (< or = 1 mg/L) compared with only 30.0% for ciprofloxacin, 31.7% for ofloxacin, 32% for fleroxacin, and 37.7% for sparfloxacin at their recommended breakpoints . No strain susceptible to ciprofloxacin was resistant to the other compounds tested. Antimicrob Agents Chemother, 1995 Aug, 39(8), 1700 - 3 Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients; Alangaden GJ et al.; To examine the mechanism of resistance to fluoroquinolones in Mycobacterium tuberculosis, we selected spontaneous fluoroquinolone-resistant mutants from a susceptible strain, H37Rv, and studied the susceptibilities of these mutants and two fluoroquinolone-resistant clinical isolates (A-382, A-564) to various fluoroquinolones and to isoniazid and rifampin . Furthermore, since mutations within the quinolone resistance-determining region of the structural gene encoding the A subunit of DNA gyrase are the most common mechanism of acquired resistance, we amplified this region by PCR and compared the nucleotide sequences of the fluoroquinolone-resistant strains with that of the susceptible strain . Fluoroquinolone-resistant mutants of H37Rv appeared at frequencies of 2 x 10(-6) to 1 x 10(-8) . For three mutants selected on ciprofloxacin, ofloxacin, and sparfloxacin, respectively, and the two clinical isolates, MICs of ciprofloxacin and ofloxacin were as high as 16 micrograms/ml, and those of sparfloxacin were 4 to 8 micrograms/ml . They displayed cross-resistance to all fluoroquinolones tested but not to isoniazid or rifampin . Sparfloxacin and FQ-A (PD 127391-0002) were the most potent fluoroquinolones . All of the fluoroquinolone-resistant strains (MICs, > or = 4 micrograms/ml) had mutations in the quinolone resistance-determining region which led to substitution of the Asp residue at position 87 (Asp-87) by Asn or Ala or the substitution of Ala-83 by Val in the A subunit of DNA gyrase . Similar mutations have been noted in other bacterial species and recently in mycobacteria . The broad resistance to fluoroquinolones that arose readily by point mutation in the laboratory and apparently during inadequate therapy, as was the case in the clinical isolates, may ultimately lead to to serious restriction of the use of these drugs in the treatment of tuberculosis. Antimicrob Agents Chemother, 1995 Aug, 39(8), 1683 - 7 Determination of robust ocular pharmacokinetic parameters in serum and vitreous humor of albino rabbits following systemic administration of ciprofloxacin from sparse data sets by using IT2S, a population pharmacokinetic modeling program; Drusano GL et al.; Robust determination of the concentration-time profile of anti-infective agents in certain specialized compartments is often limited by the inability to obtain more than a single sample from such a site in any one subject . Vitreous humor and cerebrospinal fluid are obvious examples for which the determination of concentrations of anti-infective agents is limited . Advances in pharmacodynamics have pointed out the importance of understanding the profiles of drugs in the plasma and in specialized compartments in order to dose the drugs to obtain the best patient outcomes . Advances in population pharmacokinetic modeling hold the promise of allowing proper estimation of drug penetration into the vitreous (or other specialized compartment) with only a single vitreous sample, in conjunction with plasma sampling . We have developed a rabbit model which allows multiple samples of vitreous to be obtained without breaking down the blood-vitreous barrier . We have employed this model to test the hypothesis that robust estimates of vitreous penetration by the fluoroquinolone ciprofloxacin can be obtained from a traditional intensive plasma sampling set plus a single vitreous sample . We studied 33 rabbits which were receiving 40 mg of ciprofloxacin per kg of body weight intravenously as short infusions and from which multiple plasma and vitreous samples were obtained and assayed for ciprofloxacin content by high-performance liquid chromatography . Data were analyzed by the iterative two-stage population modeling technique (IT2S), employing the iterative two-stage program of Forrest et al . (Antimicrob . Agents Chemother . 37:1065-1072, 1993) . Two data sets were analyzed: all plasma and vitreous samples versus all plasma samples and the initially obtained single vitreous sample . The pharmacokinetic parameter values identified were used to calculate the percent vitreous penetration as the ratio of the area under the concentration-time curve for the vitreous to that for the plasma . The values identified, 4% penetration for the full data set versus 3% penetration for the single vitreous sample data set, and their corresponding estimates were not statistically significantly different . We conclude that population modeling holds promise for the analysis of penetration of antimicrobiol agents into specialized spaces from which only single samples can be obtained, particularly for patients with whom robust plasma sampling can be performed. J Chromatogr B Biomed Appl, 1995 Jul 21, 669(2), 372 - 6 Simultaneous determination of theophylline, enoxacin and ciprofloxacin in human plasma and saliva by high-performance liquid chromatography; Zhai S et al.; A simple reversed-phase high-performance liquid chromatographic method has been developed for the simultaneous determination of theophylline, ciprofloxacin and enoxacin in plasma and saliva . The biological fluid samples were extracted with methylene chloride-isopropyl alcohol prior to isocratic chromatography on a Waters C18 mu Bondapak column . Ultraviolet detection was carried out at 268 nm . The assay is linear for ciprofloxacin and enoxacin (0.05-10 micrograms/ml), and theophylline (0.1-20 micrograms/ml) . The assay can be used to investigate the interaction of these two fluoroquinolones with theophylline. Allergy, 1995 Jul, 50(7), 598 - 9 Fixed eruption caused by ciprofloxacin without cross-sensitivity to norfloxacin; Lozano Ayllon M et al.; We report the case of a female patient who presented fixed exanthema following administration of ciprofloxacin . To our knowledge, only one case of fixed exanthema in response to this agent has appeared in the literature, and it was associated with cross-sensitivity to norfloxacin. J Hosp Infect, 1995 Jul, 30(3), 211 - 6 Oral ciprofloxacin as prophylaxis in gastroduodenal surgery; McArdle CS et al.; One hundred and fifty patients undergoing gastroduodenal surgery were randomly allocated to receive intravenous (iv) cefuroxime, iv ciprofloxacin or oral ciprofloxacin as prophylaxis . There were no differences in the incidence of postoperative infection complications or duration of stay among the three groups . Oral ciprofloxacin offers obvious advantages in terms of ease of administration and cost. Bone Marrow Transplant, 1995 Jul, 16(1), 183 - 5 Allogeneic BMT in a patient with CML and prior disseminated infection by mycobacterium avium complex; Hermida G et al.; A patient with chronic myeloid leukemia (CML) who developed a disseminated infection by mycobacterium avium complex (MAC) was successfully treated with rifampin, ethambutol, isoniazid, cycloserin and ciprofloxacin . Diagnosis was proven by histologic examination of hepatic biopsy and culture of the liver biopsy material . Two years later the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor . Antimycobacterial prophylaxis to MAC with ethambutol, cycloserin and ciprofloxacin was given throughout the immediate post-transplant period . On day +25 post-BMT secondary prophylaxis was changed to ciprofloxacin and clarithromycin due to hepatic toxicity . Treatment was maintained until day 100 without side effects . There was no evidence of recurrent mycobacteriosis . Eight months after BMT the patient is well, with a good performance status and chronic graft-versus-host disease (GVHD) limited to the oral mucosa . Thus, MAC infection prior to transplant need not be a contraindication to successful BMT. Am J Respir Crit Care Med, 1995 Jun, 151(6), 2006 - 9 Long-term safety of ofloxacin and ciprofloxacin in the treatment of mycobacterial infections; Berning SE et al.; Ofloxacin and ciprofloxacin are potentially useful agents for treating mycobacterial infections . We retrospectively reviewed 7 years' experience with these agents in 103 patients . Ofloxacin was used primarily to treat tuberculosis (TB), dosed to achieve 2-hour postdose serum concentrations of 8-12 micrograms/ml . Ciprofloxacin was used primarily to treat Mycobacterium avium complex (MAC) infection, dosed to achieve 2-hour post-dose serum concentrations of 4-6 micrograms/ml . Despite differences in patient characteristics, underlying disease, and concurrent medications, ofloxacin and ciprofloxacin were associated with a similar spectrum and incidence of adverse reactions . Both drugs were generally well tolerated . Adverse effects led to an ofloxacin dosage change in 1 patient (3%) and discontinuation of ofloxacin in 2 patients (6%) . Adverse effects led to a ciprofloxacin dosage change in 2 patients (3%) and discontinuation of ciprofloxacin in 5 patients (7%) . Ofloxacin and ciprofloxacin appear to be tolerated as well as or better than other "second-line" antimycobacterial drugs. Am J Clin Oncol, 1995 Jun, 18(3), 189 - 93 Pentoxifylline and ciprofloxacin in patients with myelodysplastic syndrome . A phase II trial; Nemunaitis J et al.; Tumor necrosis factor (TNF) inhibits hematopoietic cell proliferation . The combination of pentoxifylline (PTX) and ciprofloxacin (Cipro) has been previously shown to reduce circulating serum levels of TNF . In this Phase II trial 14 patients with advanced myelodysplastic syndrome were treated with PTX (2,000 mg/day) and Cipro (1,000 mg/day) in order to determine tolerability and effect on peripheral blood cell counts, progenitor cell responsiveness to cytokines and circulating serum levels of interleukin-6 (IL6) and TNF . Toxicity attributed to PTX and Cipro were limited to nausea in 4 patients . Peripheral blood cell counts, platelet transfusion requirements and red blood cell transfusion requirements did not change during administration of PTX and Cipro (daily for 28 days) . Marrow progenitor cells of patients entered into trial were less responsive to stimulation with cytokines in vitro at baseline and during the trial compared to normal volunteers . Eight patients had elevated IL6 levels before treatment with PTX and Cipro these levels did not change during therapy . Five patients had elevated TNF levels at baseline . There was a suggestion of decreased TNF levels during treatment with PTX and Cipro (P = .09) . In conclusion, PTX and Cipro was well tolerated but no evidence of efficacy was observed. Korean J Ophthalmol, 1995 Jun, 9(1), 12 - 8 Safety of intravitreally injected ciprofloxacin in phakic rabbit eyes; Kim SH et al.; This study was designed to determine the maximal safe drug concentration of intravitreal ciprofloxacin in phakic rabbit eyes . Twenty-two eyes of New Zealand pigmented rabbits received midvitreal ciprofloxacin of 100, 200, 400, 600 or 800 micrograms in BSS Plus, or BSS Plus only . Retinal toxicity was dose-dependent as determined with electroretinography, light microscopy, and transmission electron microscopy . At a dose of greater than 400 micrograms, disorganization of the outer segments was a main pathological finding in transmission electron microscopy . We evaluated retinal function by measuring the electroretinograms for a graded series of flash intensities and by fitting electroretinogram b-wave amplitudes to the Naka-Rushton equation . At a dose of greater than 600 micrograms, Rmax was significantly decreased and log K was significantly increased . N-value tended to decrease . A decrease of b-wave amplitudes caused by retinal toxicity could be detected very sensitively with lower luminance stimuli . Determination of retinal toxicity with lower luminance electroretinography revealed a significant decrease of b-wave amplitudes at a dose of greater than 400 micrograms . We concluded that a safe dose of intravitreal ciprofloxacin in phakic rabbit eyes was 200 micrograms in phakic eyes. Jpn J Antibiot, 1995 Jun, 48(6), 861 - 7 {Phototoxicity and photoallergenicity tests of T-3761}; Shibata T et al.; Phototoxicity and photoallergenicity tests of T-3761 (oral or percutaneous administration) were carried out in guinea pigs . Phototoxicity test of T-3761 (oral administration) was done in rats, too . The following results were obtained . 1 . Compared with comparative drugs in oral administration, phototoxicity of T-3761 was equal to that of ciprofloxacin, slightly stronger than that of nalidixic acid and weaker than those of ofloxacin, enoxacin, sparfloxacin and lomefloxacin . 2 . A sensibility to phototoxicity of T-3761 in rats was weaker than that in guinea pigs . 3 . Phototoxicity and photoallergenicity were not observed in application of T-3761 as 10% ointment . 4 . Photoallergenicity was not observed in oral administration of T-3761. J Clin Microbiol, 1995 Jun, 33(6), 1528 - 33 New Nocardia taxon among isolates of Nocardia brasiliensis associated with invasive disease; Wallace RJ Jr et al.; Nocardia brasiliensis, the second most frequently isolated aerobic actinomycete in the clinical laboratory, is usually associated with localized cutaneous infections . However, 22% of 238 N . brasiliensis isolates from the United States and 12% of 66 isolates from Queensland, Australia, which had been collected over a 17-year period, were associated with extracutaneous and/or disseminated diseases . Of the 62 invasive isolates, 37 (60%) were susceptible to ciprofloxacin and/or were susceptible to clarithromycin and resistant to minocycline, compared with only 6 (3%) of 242 localized cutaneous isolates . The 43 isolates with this susceptibility pattern appeared to define a new taxon . They were similar to Nocardia asteroides complex isolates clinically in proportions from persons with pulmonary (70%), central nervous system (23%), and/or disseminated diseases (37%) in the setting of corticosteroids (74%) or AIDS (14%) . This putative new taxon differed from N . brasiliensis in the hydrolysis of adenine (92 versus 4%), beta-lactamase patterns on isoelectric focusing, and the presence of two early mycolic acid-ester peaks by high-performance liquid chromatography . Restriction analysis of a 439-bp fragment of the 65-kDa heat shock protein gene revealed that N . brasiliensis and the new taxon had different restriction patterns with 8 of the 11 enzymes tested . Screening of invasive isolates of N . brasiliensis for susceptibility to ciprofloxacin will identify most isolates of the new taxon, which likely represents a new Nocardia species. Br J Ophthalmol, 1995 Jun, 79(6), 606 - 9 Topical 0.3% ciprofloxacin, norfloxacin, and ofloxacin in treatment of bacterial keratitis: a new method for comparative evaluation of ocular drug penetration; Diamond JP et al.; AIMS--This study was designed to assess the relative corneal penetration of topical drops of three antibiotics and to relate those levels to minimum inhibitory concentrations for organisms associated with bacterial keratitis . METHODS--Four drops of each of ciprofloxacin, norfloxacin, and ofloxacin (0.3% topical ophthalmic preparations) were given to 12 patients undergoing corneal transplantation . After the recipient tissue was removed, corneal drug penetration was measured using high performance liquid chromatography . RESULTS--Intracorneal concentrations of ofloxacin (geometric mean 0.81 mg kg-1) were significantly higher than both ciprofloxacin (0.60 mg kg-1; p = 0.048) and norfloxacin (0.54 mg kg-1; p = 0.012) . Ciprofloxacin and norfloxacin concentrations did not differ significantly (p = 0.33) . CONCLUSIONS--Review of the minimum inhibitory concentrations of the fluoroquinolones against ocular pathogens reveals that ciprofloxacin is more potent than ofloxacin against many bacteria; ofloxacin is in turn more potent than norfloxacin . These data favour the selection of ciprofloxacin and ofloxacin rather than norfloxacin for the empirical treatment of corneal infection . The greater potency of ciprofloxacin offsets the superior penetration of ofloxacin . There is a need for improved clinical trial data concerning the use of fluoroquinolone eyedrops in ulcerative keratitis; some encouraging data are available for ciprofloxacin but not (in humans) for norfloxacin or ofloxacin.<