Ciprofloxacin

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.

Xenobiotica, 1995 Jun, 25(6), 563 - 73
Metabolism of theophylline and its inhibition by fluoroquinolones in rat hepatic microsomes; Davis JD et al.; 1 . The effects of beta-naphthoflavone, dexamethasone, phenobarbitone and isosafrole on the metabolism of theophylline by rat liver microsomes have been studied . Only beta-naphthoflavone, a known P4501A inducer, increased the rate of 1-methylxanthine formation (3-fold), whereas all the inducers studied increased the rate of 1,3-dimethyluric acid production (2.5-3-fold) . 2 . To study the effects of a range of fluoroquinolones on theophylline metabolism, beta-naphthoflavone-induced microsomes were used, as the ratio for metabolite production rates was similar to that of untreated microsomes (4:1,3-dimethyluric acid: 1-methylxanthine at 2 mM theophylline) . High concentrations of fluoroquinolones (0.5-1.5 mM) were required to affect microsomal theophylline metabolism . 1-Methylxanthine was more sensitive to fluoroquinolone inhibition by enoxacin, ciprofloxacin, norfloxacin and pipemidic acid than 1,3-dimethyluric acid; CP67015, had a significant effect on 1,3-dimethyluric acid production only; binfloxacin had no effect on either pathway . 3 . Ethoxycoumarin, a rapidly metabolized substrate, was also investigated as a surrogate for theophylline in in vitro experiments . Fluoroquinolone inhibition of ethoxycoumarin O-de-ethylation in beta-naphthoflavone-induced microsomes was quantitatively greater but qualitatively similar to theophylline metabolism (IC50s 440-870 microM at 2 microM 7-ethoxycoumarin) . 4 . These data are comparable with previous rat experiments in vivo, indicating that enoxacin, ciprofloxacin and norfloxacin have similar intrinsic activity in the inhibition of theophylline metabolism.

J Pak Med Assoc, 1995 Jun, 45(6), 147 - 50
Ciprofloxacin in multi-resistant infections in childhood: an audit; Khan DM et al.; Ciprofloxacin is a new orally administrable fluoroquinolones, with considerable efficacy against multiresistant organisms . Its use in the paediatric age group however, is controversial because of the risk of potential articular toxicity . We retrospectively reviewed ciprofloxacin usage over a 32 week periods (June, 1991-September, 1993) in paediatric inpatients at The Aga Khan University Hospital . Ciprofloxacin was used in 21 cases, singly in 11 (52%) and in combination with other antibiotics in a further 10 (48%) . The response to therapy was adjudged as 'good' or 'fair' in 13 (62%) cases . Ciprofloxacin was the only sensitive antibiotic in 4 (19%) and resistance to it was detected in another 4 (19%) cases . Despite all efforts, adequate follow-up could only be achieved in a third of the patients . Although no toxic or side effects were detected, in view of poor follow-up and emergence of ciprofloxacin resistant strains, our experience highlights the need to regulate ciprofloxacin use in the paediatric age group.

J Assoc Physicians India, 1995 May, 43(5), 327 - 30
Comparative bioavailability of two brands of ciprofloxacin; Seth SD et al.; Twelve adult healthy volunteers participated on two occasions in a cross-over study with an interval of 30 days . The bioavailability of ciprofloxacin 500 mg administered as single oral dose was compared in preparation A (Indian, Torrent) and preparation B (Imported, Bayer) . The drug was administered early morning on an empty stomach . Blood samples were collected at 1/2,1,2,4,6,8,12 and 24 hours . Plasma levels of ciprofloxacin were determined by HPLC . Time taken to achieve peak plasma concentration (Tmax) was 2 hours (A) and 1.67 +/- 0.49 hours (B) . Maximum plasma concentration (Cmax) ranged from 1.8 to 5.1 ug/ml (mean 3.08 +/- 0.99 ug/ml) for 'A' and 2.08 to 5.5 mu g/ml (mean 3.58 +/- 1.37 mu g/me for 'B' . Area under plasma concentration time curve ranged from 30.91 to 118.27 ug/ml/hr (mean 59.97 +/- 26.68 ug/ml/hr) in 'A' and 36.52 to 108.05 (mean 62.80 +/- 22.33 ug/ml/hr) in 'B' which is more than reported in Western literature . Large bioavailability of ciprofloxacin in the present study suggests the need to be cautious while treating patients with renal problems and to use lower doses in Indian patients to achieve desirable results . However, there was no significant difference in the pharmacokinetic parameters between the two brands (Paired 't' test and Wilcoxon Sign Rank test) . It is therefore, concluded that both the preparations are comparable in terms of bioavailability.

Am J Hematol, 1995 May, 49(1), 83 - 6
Characterization of two cases of acquired transitory von Willebrand syndrome with ciprofloxacin: evidence for heightened proteolysis of von Willebrand factor; Castaman G et al.; We characterized the cause of two cases of transitory acquired von Willebrand syndrome associated with the administration of ciprofloxacin . Purified Ig from the two patients did not inhibit Ristocetin Cofactor activity or binding to collagen of normal plasma, ruling out the possibility of an inhibitor . The analysis of multimeric pattern of plasma von Willebrand Factor (vWF) showed the lack of larger multimers in both patients, with a relative decrease of all the remaining forms in the first patient . The subunit composition of plasma vWF showed a marked reduction of the native 225 Kd subunit (31.9% and 32.9%; normal range 74-86%) and an increased proportion of the 189, 176, and 140 Kd fragments . These abnormalities disappeared during the follow-up, without any specific therapy . In conclusion, a common pathophysiological basis is demonstrated in both patients, with a heightened proteolysis of plasma vWF by an unknown mechanism.

Jpn J Antibiot, 1995 May, 48(5), 665 - 70
{Affinity of T-3761 to ocular melanin and intraocular dynamics}; Hayakawa H et al.; The affinity of T-3761 to melanin was examined with synthetic melanin comparing other quinolones . The binding rates with synthetic melanin were from 37% to 48% for tosufloxacin, sparfloxacin, ciprofloxacin and norfloxacin . Binding rate of ofloxacin at 28% was lower and T-3761 was lowest at 22% . Intraocular dynamics of T-3761 and ofloxacin were investigated in pigmented rabbits after a single oral administration at a dose of 20 mg/kg . In both drugs, the concentrations in the melanin bearing tissues were higher and the disappearances from the melanin bearing tissues were more slowly than those of the non-melanin bearing tissues . T-3761 concentrations in the melanin bearing tissues were significantly lower than ofloxacin . In vitro uptake amount to melanin bearing tissue of ofloxacin was 1.4-2.4 times larger than that of T-3761.

Jpn J Antibiot, 1995 May, 48(5), 643 - 8
{Serum protein binding of T-3761}; Kitayama R et al.; We investigated the extent of the binding of T-3761 to serum protein and obtained the following results . 1 . The binding rates of T-3761 to serum protein from various animals and human were 16.9-27.7%, and a little higher than those of ciprofloxacin and ofloxacin . 2 . The binding rates of T-3761 to human serum protein were 19.1-23.8% at concentrations of 0.25-20 micrograms/ml . 3 . The binding rates of T-3761 lowered as the decrease of protein concentration . 4 . The binding rates of T-3761 (2 micrograms/ml) to human serum protein were 12.4, 21.3 and 32.1% at pH 7.0, 7.4 and 8.0, respectively, showing the effect of the pH . 5 . The binding of T-3761 to human serum protein was reversible . 6 . In vivo binding rates of T-3761 in rabbits after a single oral administration of 20 mg/kg were 26.1-33.2%, which were similar to those obtained in vitro.

Clin Infect Dis, 1995 May, 20(5), 1399 - 401
Mycobacterium xenopi infection masquerading as pulmonary tuberculosis in two patients infected with the human immunodeficiency virus; Jacoby HM et al.; Mycobacterium xenopi infections have rarely been reported among patients infected with the human immunodeficiency virus (HIV) . We recently treated two HIV-infected men, neither of whom had a history of pulmonary disease or AIDS-defining conditions, and who had M . xenopi lung infections . Both patients presented with night sweats, cough, and pleuritic chest pain . Chest radiographs showed an upper-lobe nodule in the first patient and a perihilar cavitary infiltrate in the second patient . Both patients were initially believed to have pulmonary tuberculosis and were treated accordingly; however, only M . xenopi grew on cultures of multiple respiratory specimens . This diagnosis was confirmed by cultures of biopsied lung tissue from the first patient and of fluid from a peritracheal abscess in the second patient . Both patients' clinical conditions improved after multidrug therapy (isoniazid, rifampin, pyrazinamide, ethambutol, and ciprofloxacin in the first case; isoniazid, rifampin, and pyrazinamide in the second case) . The second patient's condition improved despite in vitro resistance of his isolate to isoniazid and rifampin.

Antimicrob Agents Chemother, 1995 Apr, 39(4), 1003 - 6
Pharmacokinetics of high-dose intravenous ciprofloxacin in young and elderly and in male and female subjects; Shah A et al.; The effects of age and gender on the pharmacokinetics of high-dose intravenous ciprofloxacin in a healthy volunteer study were investigated . Plasma ciprofloxacin concentrations were higher in the elderly than in the young, and the pharmacokinetic parameters were not significantly different between the genders . Ciprofloxacin was well tolerated, with the majority of adverse events related to local reactions at the IV site.

Am J Vet Res, 1995 Apr, 56(4), 501 - 6
Pharmacokinetics and residues of enrofloxacin in chickens; Anadon A et al.; The pharmacokinetic properties of enrofloxacin were determined in broiler chickens after single IV and orally administered doses of 10 mg/kg of body weight . After IV and oral administrations, the plasma concentration-time graph was characteristic of a two-compartment open model . The elimination half-life and the mean +/- SEM residence time of enrofloxacin for plasma were 10.29 +/- 0.45 and 9.65 +/- 0.48 hours, respectively, after IV administration and 14.23 +/- 0.46 and 15.30 +/- 0.53 hours, respectively, after oral administration . After single oral administration, enrofloxacin was absorbed slowly, with time to reach maximal plasma concentration of 1.64 +/- 0.04 hours . Maximal plasma concentration was 2.44 +/- 0.06 micrograms/ml . Oral bioavailability was found to be 64.0 +/- 0.2% . Statistically significant differences between the 2 routes of administration were found for the pharmacokinetic variables--half-lives of the distribution and elimination phase and apparent volume of distribution and volume of distribution at steady state . In chickens, enrofloxacin was extensively metabolized into ciprofloxacin . Residues of enrofloxacin and the major metabolite ciprofloxacin in fat, kidney, liver, lungs, muscles, and skin were measured in chickens that received an orally administered dose of 10 mg/kg once daily for 4 days . The results indicate that enrofloxacin and ciprofloxacin residues were cleared slowly . Mean muscle, liver, and kidney concentrations of the metabolite ciprofloxacin ranging between 0.020 and 0.075 micrograms/g persisted on day 12 in chickens after dosing . However, at the time of slaughter (12 days), enrofloxacin residues were only detected in liver and mean +/- SEM concentration was 0.025 +/- 0.003 micrograms/g.

Tuber Lung Dis, 1995 Apr, 76(2), 173 - 5
Ciprofloxacin-induced renal dysfunction in patients with mycobacterial lung infections; Yew WW et al.; 3 patients with mycobacterial lung infections, one due to Mycobacterium avium-intracellulare and 2 due to M . tuberculosis, developed ciprofloxacin-induced acute renal dysfunction while receiving the drug together with other antimycobacterial agents . These episodes took place 8-10 days after commencement of therapy and recovered spontaneously after cessation of all antimycobacterial drugs for 2-8 weeks . No recurrence was noted when patients were restarted on regimens that did not contain ciprofloxacin.

Kansenshogaku Zasshi, 1995 Apr, 69(4), 404 - 7
{Effect of ciprofloxacin on contractile responses of canine airway smooth muscle}; Tagaya E et al.; To elucidate whether the new quinolone ciprofloxacin affects cholinergic neuto-effector transmission in the airway, we studied canine isolated bronchial segments under isometric conditions in vitro . Intrapulmonary lobar or segmental bronchi were suspended in the organ chambers filled with Krebs-Henseleit solution, and the isometric tension was continuously recorded by a force-displacement transducer . Addition of ciprofloxacin (2 x 10(-3) M) attenuated the contractile responses to electrical field stimulation (EFS), so that the stimulus frequency required to produce a half-maximal contraction (ES50) increased from 1.2 +/- 0.2 to 1.5 +/- 0.2 Hz (p < 0.05), whereas it was without effect on those to exogenously administered acetylcholine . The decrease in the EFS-induced contraction produced by ciprofloxacin was concentration-dependent and was not influenced by propranolol or tetraethylammonium, but partially inhibited by ouabain . These results suggest that ciprofloxacin may inhibit cholinergic neuro-effector transmission in the airway smooth muscle by inhibiting the exocytotic release of acetylcholine, probably involving the stimulation of Na(+)-K(+)-ATPase and concomitant repolarization/hyperpolarization of cholinergic nerve terminals.

Clin Pharmacol Ther, 1995 Apr, 57(4), 446 - 54
Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans; Capecchi PL et al.; OBJECTIVE: To study the possibility that the penetration of the antibiotic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be associated with some changes in cell reactivity . DESIGN: Superoxide anion and chemiluminescence generation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) were studied ex vivo in 12 healthy volunteers (mean age, 53.15 +/- 16.3 years; mean body weight, 71.23 +/- 6.9 kg) at fixed intervals up to 72 hours from the administration of a single oral dose of 250 mg ciprofloxacin . Cytosolic free calcium levels ({Ca2+}i) in resting and stimulated cells were also evaluated . The dynamic parameters of the effects on PMNs were compared with the kinetic profile of the drug in plasma and in PMNs . RESULTS: Superoxide generation induced by the stimulating agents increased significantly, reaching a peak after 12 hours (+116% {p < 0.001} for fMLP and +66% {p < 0.05} for PAF) . Similarly, chemiluminescence production showed a threefold increase in the response to the stimulating agents 12 hours after drug administration (p < 0.001) . The increase in {Ca2+}i in stimulated PMNs was significantly potentiated (p < 0.001) . The mathematic analysis of the effects of ciprofloxacin showed that time to maximal activity was between 10.4 hours (PAF-dependent {Ca2+}i increase), and 15 hours (fMLP-induced superoxide anion and chemiluminescence production) . The ratio of PMNs to plasma ciprofloxacin concentration increased progressively, from 0.5 at 30 minutes to 10.4 after 24 hours . In addition, time to maximal activity and half-life differed in PMNs and in plasma (4.66 versus 1.90 hours and 13.03 versus 7.28 hours, respectively) . CONCLUSIONS: Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to fMLP and PAF . The levels of the drug in the cells were greater and more sustained in the time than those in plasma.

Antibiot Khimioter, 1995 Apr, 40(4), 30 - 3
{Effect of ciprofloxacin on luminol-dependent chemiluminescence and adhesion of leukocytes}; Iordanova AI et al.; The in vitro effect of ciprofloxacin on the luminol-dependent chemiluminescence and adherence of polymorphonuclear leukocytes of guinea pigs was studied with the use of a wide variety of the drug concentrations from 0.1 to 1000 micrograms/ml under two different conditions: during incubation of the cells in the presence of the drug different concentrations and after the cell washing to remove ciprofloxacin . In concentrations of 1 to 100 micrograms/ml ciprofloxacin lowered the chemiluminescence at the average by 20 per cent and in a concentration of 1000 micrograms/ml the drug completely inhibited it . In concentrations of 0.1 to 100 micrograms/ml ciprofloxacin lowered as well the leukocyte adherence.

Zhongguo Zhong Xi Yi Jie He Za Zhi, 1995 Apr, 15(4), 225 - 7
{Experimental study on anti-duck hepatitis B viral effect of Phyllanthus urinaria of different areas and combined therapy with other drugs}; Chen YX et al.; The duck hepatitis B virus model was treated with phyllanthus urinaria of different area and combined with Sophora flavesceus as well as ciprofloxacin once a day for one month, the results indicated: Guangxi and Yunnan Phyllanthus could lower the serum DHBV DNA significantly (P < 0.05), but Chongqing Phyllanthus couldn't . And the amount of serum DHBV DNA rose a week after stopping of Yunnan Phyllanthus . The antiviral effect of Guangxi Phyllanthus combined with ciprofloxacin seems to be strengthened (P < 0.05).

Vestn Oftalmol, 1995 Apr-Jun, 111(2), 8 - 10
{Use of siflox (ciprofloxacin) in paratrachoma and assessment of its effectiveness by immunoenzyme analysis}; Maichuk IuF et al.; The possibility of using an antibiotic ciprofloxacin quinolone (siflox) in combined therapy of paratrachoma was investigated . Fifty patients with acute and subacute paratrachoma were included in the study . The drug efficacy was assessed by clinical results and laboratory findings: by the time course of the levels of Chlamydia trachomatis antigen in smears from the conjunctiva, measured by enzyme immunoassay (EIA) using the Abbott kit . The results indicated a high efficacy of siflox in combination with local application of tetracycline ointment; such treatment helped shorten the treatment period . EIA proved to be not only a highly sensitive and effective method for the diagnosis of chlamydial infection of the eyes, but permitted assessment of changes in the levels of the antigen over the course of treatment and, hence, helped assess the treatment efficacy.

Diagn Microbiol Infect Dis, 1995 Apr, 21(4), 209 - 13
Modifications for disk diffusion susceptibility testing criteria of clinafloxacin (CI-960, AM-1091, PD127371) and fleroxacin (Ro 23-6240, AM-833) following studies with a challenge panel of ciprofloxacin-resistant clinical isolates; Jones RN et al.; A collection of ciprofloxacin-resistant organisms (200 strains) was developed among 300 total test strains to "challenge" the initial interpretive criteria developed for clinafloxacin (formerly CI-960), fleroxacin (formerly Ro 23-6240, AM-833), and ciprofloxacin . Generated results indicate the necessity for modified criteria for disk diffusion tests (5-micrograms disks) as follows: for clinafloxacin, susceptible at > or = 21 mm ( < or = 1 microgram/ml) and resistant at < or = 17 mm ( > or = 4 micrograms/ml), or susceptible at > or = 19 mm ( < or = 2 micrograms/liter) and resistant at < or = 15 mm ( > or = 8 micrograms/ml); for fleroxacin, susceptible at > or = 16 mm ( < or = 2 micrograms/ml) and resistant at < or = 11 mm ( > or = 8 micrograms/ml); and for ciprofloxacin, resistant at < or = 17 mm > or = 4 micrograms/ml) . These modifications maximize total absolute interpretive accuracy between the standardized test methods, especially minimizing the potential for false susceptibility (very major errors) when testing truly resistant isolates . The clinafloxacin spectrum was widest against these resistant isolates, and the other two tested fluoroquinolones (ciprofloxacin, fleroxacin) possessed comparable overall spectrums of activity, although ciprofloxacin was generally more active on a weight basis . We urge the rapid acceptance of these criteria to improve the accuracy of the widely used National Committee for Clinical Laboratory Standards method for disk diffusion tests.

Rev Neurol (Paris), 1995 Apr, 151(4), 286 - 7
{Exacerbation of myasthenia gravis by pefloxacin}; Vial T et al.; Pefloxacine 800 mg single dose was given as routine treatment after a cystomanometric examination to a 45-year-old woman with a 30-month history of generalized myasthenia gravis . One hour after, the patient developed exacerbation of myasthenia gravis with bilateral ptosis and an increased generalized weakness . She experienced a rapid improvement during the next 8 hours and physical examination returned to normal within one day . No additional factors which might have contributed to the exacerbation of myasthenia gravis were found . The report of exacerbation of myasthenia gravis with other antibiotic belonging to the group of fluoroquinolones (ciprofloxacin, norfloxacin and ofloxacin) prompt us to recommend caution with the use of all fluoroquinolones in myasthenic patients.

Cornea, 1995 Mar, 14(2), 152 - 6
Corneal tissue levels of topically applied ciprofloxacin; Price FW Jr et al.; The effectiveness of the fluoroquinolone ciprofloxacin is dependent on stromal drug concentrations which exceed the minimum inhibitory concentration90 (MIC90) . The purpose of this study is to compare corneal tissue ciprofloxacin levels in patients exposed to three ciprofloxacin dosing regimens before undergoing penetrating keratoplasty . Thirty-one patients were assigned to one of three treatment groups . Group 1 followed a ciprofloxacin dosing regimen compatible with home use {two drops of 0.3% ciprofloxacin (Ciloxan; Alcon Laboratories, Fort Worth, TX, U.S.A.) every 4 h over a 24-h period} . Groups 2 and 3 followed a more tightly controlled dosing regimen designed for a health-care setting (two drops of Ciloxan applied by a trained professional every 15 min over a 4-h period) . In groups 1 and 2, corneal epithelium was left intact, whereas in group 3 corneas were abraded . Corneal tissue samples were surgically obtained . Excised buttons were frozen and Ciloxan concentration determined by high-pressure liquid chromatography . Ciloxan corneal tissue concentrations (mean +/- SD) were 8.82 +/- 8.24 micrograms/g tissue in group 1, 166.20 +/- 336.94 micrograms/g tissue in group 2, and 938.30 +/- 1,081.51 micrograms/g tissue in group 3 . Ciloxan penetration can be improved by administering the drug in a controlled setting at 15-min intervals over a 4-h period . Individual Ciloxan concentrations exceeded the MIC90 for most key ocular pathogens despite wide variability in all experimental groups.

Pharmacotherapy, 1995 Mar-Apr, 15(2), 236 - 45
Variable disposition of ciprofloxacin in critically ill patients undergoing continuous arteriovenous hemodiafiltration; Fish DN et al.; Continuous arteriovenous hemodiafiltration (CAVHD) is being used increasingly in critically ill patients with acute renal failure (ARF) . We prospectively evaluated extracorporeal and total systemic clearances (ClCAVHD and Cls) of ciprofloxacin during CAVHD in four patients with severe ARF to assess the adequacy of drug dosing . Ciprofloxacin serum and ultrafiltrate concentrations were measured by high-performance liquid chromatography . The ClCAVHD accounted for approximately 5.9% (range 2.8-11.6%) of Cls of ciprofloxacin . However, large variability in serum concentrations was observed with the normally recommended dose of 400 mg/day, and doses of up to 800 mg/day were required to maintain concentrations suitable for treatment of serious infections . High daily doses of ciprofloxacin required in these patients are likely related to altered pharmacokinetics in serious illness as well as to the increased extracorporeal clearance during CAVHD . Clinical studies to define appropriate dosing recommendations for ciprofloxacin during CAVHD are necessary to guide clinicians in optimum drug use.

Br J Clin Pharmacol, 1995 Mar, 39(3), 305 - 11
The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects; Batty KT et al.; 1 . The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects . 2 . Subjects were given a single oral dose of theophylline (3.4 mg kg-1), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily . 3 . Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 +/- 6.42 ml kg-1 h-1 (95% confidence limits -12.66, -2.79)) . Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 +/- 0.7 ml kg-1 h-1 (-2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 +/- 3.7 ml kg-1 h-1 (-17.2, -8.1)) . 4 . Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin . Group A subjects showed only slight inhibition of 1-demethylation (-12.8 +/- 5.5% (-21.5, -4.0)), while group B subjects showed a significantly greater inhibition of 1-demethylation (-49.9 +/- 9.8% (-62.1, -37.7)), 3-demethylation (-44.8 +/- 8.6% (-55.4, -34.1)) and 8-hydroxylation (-27.0 +/- 3.7% (-31.6, -22.4)) . 5 . The results suggest that inter-individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter-individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4 . 6 . The interaction between ciprofloxacin and theophylline can be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Ann Pharmacother, 1995 Mar, 29(3), 257 - 9
Suspected ciprofloxacin-induced hepatotoxicity; Villeneuve JP et al.; OBJECTIVE: To report a case of probable ciprofloxacin-induced hepatotoxicity . CASE SUMMARY: A 44-year-old woman developed severe hepatitis 3 weeks after initiation of a 7-day course of oral ciprofloxacin therapy . Liver biopsy showed severe hepatic necrosis, and other causes of liver injury were excluded . Liver function test results returned to normal 4 months after the appearance of jaundice . DISCUSSION: The time course of events suggested that ciprofloxacin was the cause of severe hepatitis in this patient, and other causes of hepatitis were ruled out . Hepatotoxicity has been reported with other fluoroquinolone antibiotics, and there have been previous unpublished reports to the manufacturer of possible hepatotoxicity caused by ciprofloxacin . CONCLUSIONS: It is suggested that ciprofloxacin can cause severe hepatic injury and that healthcare providers should be aware of this possible adverse drug reaction.

Antibiot Khimioter, 1995 Mar, 40(3), 10 - 5
{Multifactor analysis of ciprofloxacin action on the content of various classes of antibodies to EV vaccine fraction 1 and hemagglutinins}; Iordanova AI et al.; The action of ciprofloxacin on the content of antibodies of the IgG, IgM and IgA classes in the blood serum of mice immunized by the EV vaccine fraction 1 as well as on the content of hemagglutinins to sheep erythrocytes was studied in a multifactor analysis with the use of a wide variety of the doses and administration times . In the doses corresponding to the average therapeutic ones ciprofloxacin increased the content of the antibody classes and especially that of IgG . When administered prior to the immunization the antibiotic stimulated the production of the hemagglutinins.

Pharm Res, 1995 Feb, 12(2), 257 - 62
Effect of norfloxacin on theophylline disposition: a comparison with other fluoroquinolones; Davis JD et al.; The effects of norfloxacin (NOR), at steady-state plasma concentrations of 0-32 mg.l-1, on the plasma clearance of a 6 mg.kg-1 i.v . bolus dose of theophylline (THEO) in the male Sprague-Dawley rat have been studied . The effects were characterised by a Ki value (Ki = 12 microM), which was comparable with Ki values obtained previously under identical conditions for ciprofloxacin, but higher than that obtained for enoxacin . The distributional characteristics, volume of distribution and liver to plasma concentration ratio, were very similar for the three compounds . The only marked pharmacokinetic differences were in hepatic clearance, where there was a rank order NOR > ciprofloxacin > enoxacin, a reverse of the order in the reduction of THEO clearance seen in clinical studies . The advantages of using the steady-state experimental design described here are that equivalent concentrations are utilised to compare related drugs and differences in pharmacokinetics are accounted for, to allow a direct comparison of potency . This information, together with additional pharmacokinetic considerations, suggests that the different effects on THEO clearance seen in the clinic for NOR, ciprofloxacin and enoxacin are not solely due to differences in inhibitory potency, but also involve differences in hepatic clearance and hence systemic availability of the fluoroquinolones.

J Clin Pharm Ther, 1995 Feb, 20(1), 45 - 6
Prolonged bleeding time during ciprofloxacin therapy; Pilmore HL et al.; Ciprofloxacin is a broad spectum quinolone antibiotic . Side effects reported include nausea and other gastrointestinal symptoms; skin and musculoskeletal side effects may also occur . No bleeding abnormalities or alteration in coagulation have been documented . We report a case where ciprofloxacin appeared to contribute to an idiosyncratic prolongation of bleeding time although a rechallenge 8 months later did not reproduce the effect . Moreover, subsequent investigation of the influence of ciprofloxacin on bleeding parameters in 10 healthy volunteers demonstrated no alterations in bleeding parameters.

Arch Toxicol, 1995, 70(2), 124 - 6
In vitro effect of ciprofloxacin on HT-29 human colon carcinoma cell line: assessment of cell proliferation by thymidine uptake and silver nucleolar organizer regions (AgNOR) histomorphometry; Rabau M et al.; In an in vitro study, the effect of ciprofloxacin was examined on proliferation of HT-29 human colon carcinoma cell line . Cell proliferation was measured by 3H-thymidine uptake and silver nucleolar organizer region (AgNOR) histomorphometry . A significant increase in {3H}thymidine incorporation (p < 0.05) parallel with a significant increase in the mean AgNOR clusters/cells (p < 0.01) was noted after 5 days of cell exposure to ciprofloxacin . It is suggested that the assessment of AgNOR variables is useful in examination of quinolone effect on HT-29 human colon carcinoma cell proliferation.

Ann Oncol, 1995, 6 Suppl 4, 33 - 7
High-dose chemotherapy for breast cancer: clinical advantages of autologous peripheral blood progenitor cells (PBPC) compared with autologous bone marrow transplantation (ABMT); Martin M; Peripheral blood progenitor cell (PBPC) autografts have a number of advantages over autologous bone marrow transplantation (ABMT) as haematopoietic support after high-dose chemotherapy in patients with breast cancer . These may include less contamination by tumour cells, reduced morbidity and mortality and additional dose escalation of chemotherapy . A dose-escalation study is described using recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim) primed PBPC support and post-infusion filgrastim for patients with high-risk or metastatic breast cancer . The regimen involved the use of cyclophosphamide, thiotepa and carboplatin at five dose levels . The main problem to emerge was organ toxicity induced by chemotherapy or sepsis . Patients receiving higher levels of chemotherapy were therefore allocated or not to an additional regimen involving pentoxifylline, ciprofloxacin and dexamethasone in an attempt to inhibit tumour necrosis factor alpha (TNF-alpha) which is believed to be one of the principal mediators of chemotherapy-related organ toxicity . The incidence of bilirubin elevations, weight gain > 5% and veno-occlusive disease (VOD) was lower in patients receiving the 'anti-TNF' therapy . The simultaneous use of PBPC support and 'anti-TNF' therapy therefore allows a substantial increase in chemotherapy dosage . Further studies with larger patient numbers are required to show whether this decreased toxicity also produces increased patient survival.

Drugs, 1995, 49 Suppl 2, 112 - 4
Quinolones in the elderly; Bergan T; Aging results in a number of physiological changes that can affect drug disposition; these include reduced gastric acidity, decreased intestinal motility, lower lean body mass, and reduction in renal function . The age-related decline in renal function is the most important of these factors when administering quinolones to elderly patients . Elimination half-life (t1/2) values are prolonged in proportion to the degree to which the compound is normally eliminated by the renal route . Thus, age-related increases in t1/2 occur to a greater degree with ofloxacin (80 to 90% renal elimination) than with ciprofloxacin, which is also excreted by the gastro-intestinal route . Norfloxacin, pefloxacin, and sparfloxacin may also be eliminated to a substantial degree by the transintestinal route, as their excretion is not substantially affected by severe renal impairment . Prolonged drug elimination in the elderly can result in an increased incidence of adverse effects . Ofloxacin causes a higher frequency of drug-related events in the elderly, presumably reflecting the prolonged serum t1/2 and higher serum concentrations, and consequently higher tissue levels in this age group . Indeed, dosage reduction is recommended when treating elderly patients with ofloxacin, but does not appear necessary on the basis of advanced age for ciprofloxacin, norfloxacin and pefloxacin.

Kekkaku, 1995 Jan, 70(1), 31 - 5
{A case of Mycobacterium fortuitum pulmonary disease in a healthy young woman successfully treated with ciprofloxacin and doxycycline}; Tasaka S et al.; A 22 year-old woman was admitted to our hospital complaining of subtle fever and productive cough . She did not smoke and had no underlying disease . Her chest radiograph showed infiltration in the right upper lung field . A diagnosis of Mycobacterium fortuitum pulmonary disease was made on the basis of isolation of M . fortuitum from repeated sputum cultures . On admission, we administered standard antimycobacterial agents, but found the M . fortuitum isolated in this case to be completely resistant to them . We then administered antibiotics including 600 mg of ciprofloxacin and 200 mg of doxycycline . The pneumonic findings on chest X-ray and her clinical symptoms gradually improved thereafter . The in vitro susceptibility tests confirmed the efficacy of ciprofloxacin and doxycycline . We concluded that these drugs contributed significantly to improve the disease.

Transpl Int, 1995, 8(2), 96 - 102
Enhancement of the immunosuppressive effect of cyclosporin A by ciprofloxacin in a rat cardiac allograft transplantation model; Riesbeck K et al.; Ciprofloxacin hyperinduces interleukin-2 production in stimulated human and mouse lymphocytes . In this study, an enhanced and prolonged interleukin-2 response was also detected in polyclonally stimulated rat splenocytes in the presence of ciprofloxacin (5-80 micrograms/ml) compared to control cells without any antibiotic . Ciprofloxacin was able to counteract the immunosuppressive effect of 10 ng/ml cyclosporin A (CyA) but did not interfere with higher CyA concentrations . In parallel, ciprofloxacin did not influence thymidine uptake in mixed lymphocyte reactions in the presence of CyA . To obtain an in vivo application of these findings, graft survival was studied by performing rat cardiac allograft transplantations in the presence or absence of CyA . Brown Norway rats served as donors and Wistar Furth rats as recipients . Ciprofloxacin was injected intraperitoneally either at a high-dose regimen (240 mg/kg per 24 h) into rats every 8th h starting 1 day before transplantation until day 21 or graft loss, or it was injected at a low and clinically relevant dose regimen (45 mg/kg per 24 h) until day 9 . CyA was administered orally (10 mg/kg per 24 h) from day 1 through day 9 . Ciprofloxacin given alone at a high-dose regimen resulted in a median graft survival of 14.8 days, which was significantly longer than graft survival in rats without treatment (median 8.0 days) . A low-dose regimen of ciprofloxacin alone did not affect graft survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Kansenshogaku Zasshi, 1995 Jan, 69(1), 28 - 32
{Chemoprophylaxis of bacterial infections in granulocytopenic patients with new quinolone: a comparison of trimethoprim-sulfamethoxazole (ST) alone with ST plus ciprofloxacin}; Murase T; Fifty-three granulocytopenic patients were studied in a randomized trial comparing trimethoprim-sulfamethoxaxole (ST) alone with ST + ciprofloxacin (CPFX) for prevention of bacterial infections . Seventeen febrile episodes occurred in 24 patients receiving ST alone, and 9 febrile episodes occurred in 29 patients receiving ST + CPFX . ST + CPFX was significantly effective than ST alone (p < 0.005) . Although ST alone was effective to prevent infections in moderately granulocytopenic patients, it could not prevent infections in severely granulocytopenic patients whose minimal granulocyte count was less than 250/microliters during prophylactic treatment . In contrast, ST + CPFX was effective in severely as well as in moderately granulocytopenic patients . Clinically significant adverse reactions were not observed in both regimens . These results suggest that combination with ST and CPFX is more efficacious than ST alone for the prevention of bacterial infections in granulocytopenic patients.

Gen Hosp Psychiatry, 1995 Jan, 17(1), 47 - 53
The role of ciprofloxacin in a patient with delirium due to multiple etiologies; Farrington J et al.; A 40-year-old female with a lumbar drain was admitted to the neurosurgery service with a bacterial meningitis . During the course of her treatment with multiple central nervous system (CNS) active medications, the patient became disoriented and agitated with visual hallucinations and generalized myoclonus . A psychiatric consultation was requested . The case is presented and discussed within the context of the importance of understanding etiological mechanisms in treating and reversing delirium . The fluoroquinolone agent ciprofloxacin was considered to be the primary etiology of the patient's delirium . This class of medication as a cause of altered mental status is discussed.

Clin Infect Dis, 1995 Jan, 20(1), 174 - 5
Relapse of tularemia after aminoglycoside therapy: case report and discussion of therapeutic options; Risi GF et al.; We describe a patient with ulceroglandular tularemia who initially responded to therapy with gentamicin but then clinically relapsed . Ciprofloxacin was subsequently given for 28 days, and the patient was clinically cured . Aminoglycosides have been considered the drugs of choice in the treatment of tularemia; however, potential alternative treatments do exist . We review the English-language literature on this topic.

J Clin Microbiol, 1995 Jan, 33(1), 146 - 8
Suggested modifications for disk diffusion susceptibility testing criteria for levofloxacin and sparfloxacin following tests with a predictor panel of ciprofloxacin-resistant clinical isolates; Sutton LD et al.; A predictor panel of 300 clinical bacterial isolates (200 resistant to ciprofloxacin) was used to compare 5-micrograms disk diffusion test results with the MICs of ofloxacin (control), levofloxacin, and sparfloxacin . Regression analysis demonstrated high correlations between the methods for all three fluoroquinolones (r > or = 0.95) . In order to minimize disk diffusion testing errors among the fluoroquinolone-resistant strains, the following modifications to previously proposed or published interpretive criteria were suggested: for levofloxacin, susceptible at > or = 17 mm (< or = 2 micrograms/ml) and resistant at < or = 13 mm (> or = 8 micrograms/ml); for sparfloxacin, susceptible at > or = 20 mm (< or = 1 microgram/ml) and resistant at < or = 16 mm (> or = 4 micrograms/ml) . The study control drug, ofloxacin, did not appear to possess a significant error rate (5% minor error) when fluoroquinolone-resistant strains were tested, and no modifications were proposed . Under these proposed interpretive criteria, the absolute categorical agreements between standardized susceptibility testing methods for levofloxacin and sparfloxacin results were 91.3 and 94.0%, respectively (< or = 0.3% major errors and nil very major errors).

Antimicrob Agents Chemother, 1995 Jan, 39(1), 99 - 102
Intestinal elimination of sparfloxacin, fleroxacin, and ciprofloxacin in rats; Rubinstein E et al.; The intestinal transepithelial elimination of sparfloxacin and fleroxacin was compared with that of ciprofloxacin in a rat model following a single parenteral administration of 25 mg of each of the antibiotics per kg of body weight . All three fluoroquinolones were eliminated through the small intestine . Ciprofloxacin was eliminated in the proximal jejunum at a rate of 1.97 +/- 0.70 micrograms/cm2, while the elimination rates of fleroxacin and sparfloxacin were 0.64 +/- 026 and 0.21 +/- 0.10 micrograms/cm2, respectively, over a 90-min collection period . In the ileum, the elimination rates of ciprofloxacin, fleroxacin, and sparfloxacin over the same period were 1.44 +/- 0.77, 1.00 +/- 0.33, and 0.41 +/- 0.26 micrograms/mc2, respectively . These data suggest that these fluoroquinolones undergo a transepithelial elimination process in the small intestine . This route of elimination may be important in the therapy of bacterial diarrhea.

Antimicrob Agents Chemother, 1995 Jan, 39(1), 150 - 4
Modification of immune response in mice by ciprofloxacin; Jimenez-Valera M et al.; Some studies have suggested that the addition of ciprofloxacin to in vitro cultures of mitogen-stimulated lymphocytes exerts inhibitory effects on cell cycle progression and immunoglobulin (Ig) secretion . We tested the effects of this drug on some immunity parameters in BALB/c mice . Mice treated intraperitoneally with ciprofloxacin (10 mg/kg of body weight per day) for 3 consecutive days and immunized with sheep erythrocytes 24 h after the last injection showed significant suppression of hemolytic IgG-forming cells, whereas the response of IgM-forming cells remained unchanged . When treatment lasted 7 days the response of antibody-forming cells was not modified . When the 3-day treatment was started at 24 h after immunization with sheep erythrocytes, the response of IgM-forming cells was increased, whereas the response of IgG-forming cells was suppressed . Delayed-type hypersensitivity to sheep erythrocytes was significantly suppressed in animals that received the 3-day treatment with ciprofloxacin and were immunized subcutaneously 24 h after the last injection . In vitro proliferation of lymphocytes from ciprofloxacin-treated mice in response to either lipopolysaccharide or concanavalin A was also suppressed . Leukopenia and an increase in the level of granulocyte-macrophage colony-forming cells in bone marrow were also observed in ciprofloxacin-treated mice . These results, together with those from other reports, suggest that modification of the biological responses by ciprofloxacin is a complex phenomenon that may be influenced by several factors.

Bull World Health Organ, 1995, 73(3), 305 - 13
Therapeutic algorithms for the management of sexually transmitted diseases at the peripheral level in Côte d'Ivoire: assessment of efficacy and cost; La Ruche G et al.; In the acquired immunodeficiency syndrome (AIDS) era, adequate management of sexually transmitted diseases (STDs) is a primary concern in Africa . Assessed in this study is the clinical efficacy and feasibility of WHO-recommended therapeutic algorithms for genital discharges and ulcers, diagnosed without laboratory tests, for use at the primary health care level . Drugs were sold on a cost-recovery basis and included intramuscular ceftriaxone and oral ciprofloxacin for single-dose therapy of gonorrhoea and chancroid . During April 1993 in 10 peripheral health care centres in Abidjan, Cote d'Ivoire, a total of 207 patients were followed up, including 89 cases of male urethritis, 92 cases of vaginal discharges and 26 cases of genital ulcers; clinical success, assessed 7 days after the onset of therapy, was, respectively, 92%, 87%, and 100% . Less than 10% of the 207 patients were referred to the next care level, an acceptable rate from a public health point of view . Medical adherence to the algorithms was excellent for urethral discharges and genital ulcers but poor for vaginal discharges, partly because of intentional therapeutic modifications, without detriment to success . For drugs, the average cost per cure was 1546 francs CFA (US$ 5.60) (maximum, 2980 francs CFA (US$ 10.70) . Effective and affordable treatments for STDs are necessary for their realistic case management in Africa.

Drugs Exp Clin Res, 1995, 21(2), 79 - 83
Ciprofloxacin in the management of pulmonary tuberculosis in the face of hepatic dysfunction; Yew WW et al.; Twenty-five patients who had extensive pulmonary tuberculosis and hepatitis induced by antituberculosis drugs were treated with ciprofloxacin together with other relatively non-hepatotoxic drugs, either during the interim phase awaiting recovery of liver function in some, or as definitive therapy as required by the compromised hepatic status of others . Only 22 patients were assessable . All tolerated ciprofloxacin well during the phase of hepatic dysfunction . All patients improved with these ciprofloxacin-containing regimens, but the optimal dosage, specific efficacy and long-term safety of the drug in such cases require further evaluation.

Lancet, 1994 Dec 3, 344(8936), 1537 - 9
Randomised trial of single-dose ciprofloxacin for travellers' diarrhoea; Salam I et al.; Diarrhoea is the most common illness affecting travellers to developing countries . Our study was designed to compare the efficacy of a single 500 mg dose of ciprofloxacin with placebo for treatment of acute diarrhoea in travellers . British troops who were within their first 8 weeks of deployment in Belize and who presented within 24 h of the onset of diarrhoea, were randomized to receive either ciprofloxacin 500 mg or placebo . Every subject recorded the number and consistency of stools and presence of any other associated symptoms for 72 h or until recovery . Of 88 subjects enrolled, 83 were evaluable, of whom 45 received ciprofloxacin and 38 placebo . Groups did not differ with regard to duration or severity of diarrhoea at randomisation . Mean (SE) duration of diarrhoea, as assessed by time to the last liquid and last unformed stool, was reduced from 50.4 (4.5) h and 53.5 (4.4) h, respectively, in the placebo group to 20.9 (3.4) h and 24.8 (3.8) h in those receiving ciprofloxacin (p < 0.0001) . Mean number of liquid stools was reduced from 11.4 (1.2) in the placebo group to 5.0 (0.7) in the ciprofloxacin-treated group (p < 0.0001) . The cumulative percentages of subjects with no unformed stool after 24 h, 48 h, and 72 h were, respectively, 64%, 82%, and 93% in the ciprofloxacin group and 11%, 42%, and 79% in the placebo group (p < 0.0001, p < 0.001, and not significant, respectively) . A single 500 mg dose of ciprofloxacin was an effective empirical treatment for reducing the duration and severity of diarrhoea in travellers . The regimen should maximise compliance and reduce the cost and duration of therapy.

Br J Clin Pharmacol, 1994 Dec, 38(6), 573 - 6
Inhibition of caffeine metabolism by ciprofloxacin in children with cystic fibrosis as measured by the caffeine breath test; Parker AC et al.; The caffeine breath test was carried out in six children with cystic fibrosis, before and during a course of ciprofloxacin . There was a significant decrease in the 2 h cumulative labelled CO2 exhaled during ciprofloxacin treatment, mean difference (s.d.) -5.2(3.3)%, P < 0.02 . The results suggest an inhibition of 3-N-demethylation of caffeine (CYP1A2 enzyme activity) by ciprofloxacin . Ciprofloxacin may cause significant drug interactions in children with cystic fibrosis . The caffeine breath test can be used to study drug interactions involving CYP1A2 in children.

J Clin Pharm Ther, 1994 Dec, 19(6), 335 - 9
Effect of famotidine on ciprofloxacin pharmacokinetics after single intravenous and oral doses in rats; al-Khamis KI et al.; The effect of intravenous (3.5 mg/kg) and oral (5 mg/kg) famotidine on ciprofloxacin pharmacokinetics after single (i.v.) intravenous (5 mg/kg) and oral (20 mg/kg) doses were examined in the rat . Famotidine co-administration significantly increased the terminal elimination half-life of ciprofloxacin (54% and 29% following i.v . and oral administration, respectively) and tended to reduce the total body clearance by 27% and 34% following i.v . and oral routes, respectively . The area under the plasma concentration-time curve and the mean residence time in the body after i.v . and oral doses were significantly increased following famotidine co-administration . No changes in the steady-state apparent volume of distribution was observed after i.v . administration . The maximum plasma concentration and the time to peak concentration after oral dosing were also unaffected . These results suggest a possible reduction in the total clearance of ciprofloxacin, owing to inhibition of its renal tubular excretion by famotidine . Further studies are warranted to determine whether this interaction occurs in humans.

Gynecol Oncol, 1994 Dec, 55(3 Pt 1), 415 - 20
Chemoprophylaxis with oral ciprofloxacin in ovarian cancer patients receiving taxol; Carlson JW et al.; The purpose of this study was to review the clinical outcomes and cost of administration of a prophylactic antibiotic compared to G-CSF for the prevention of neutropenic morbidity associated with taxol . The study group was composed of 62 patients with ovarian cancer who received a 24-h infusion of a taxol-based regimen at doses less than or equal to 175 mg/m2 between June 1992 and April 1994 . The records were retrospectively reviewed and the patients were grouped and analyzed according to the management of their myelosuppression . Group I patients (n = 29) were observed until their absolute neutrophil count (ANC) was less than 500/microliters and then were placed on ciprofloxacin 500 mg orally twice a day until their ANC was 1,000/microliters . Group II patients (n = 15) received G-CSF from Day 2 until the ANC was greater than 10,000/microliters beginning with their first cycle . Group III patients (n = 18) received their taxol regimen without either ciprofloxacin or G-CSF . Two hundred eighty-two taxol-based chemotherapy cycles were administered to these 62 patients . There was no statistically significant difference between the groups concerning disease status as measured by age, stage, performance status, dose intensity, or number of previous regimens . There were two episodes of febrile neutropenia in Group I and three episodes in Group II . Group III had 15 episodes of febrile neutropenia . The estimated cost of the different prophylactic regimens was $5,215.00 for Group I versus $104,000.00 for G-CSF in Group II . Within the three groups, there were 27 patients with an episode of febrile neutropenia (n = 20) or prolonged myelosuppression (n = 7) that were followed for an additional 104 taxol cycles . Twenty-four of these patients received G-CSF prophylaxis with intermittent ciprofloxacin and three received only ciprofloxacin . There were eight more episodes of febrile neutropenia in the patients receiving G-CSF . There were no additional febrile episodes on cycles prophylaxed with ciprofloxacin . There was no septic mortality . For patients receiving a 24 h infusion of taxol at doses less than 175 mg/m2, ciprofloxacin given through the ANC nadir may be effective in preventing febrile morbidity . A prospective randomized trial is underway to evaluate this approach.

Tidsskr Nor Laegeforen, 1994 Nov 10, 114(27), 3179 - 81
{Hemolytic-uremic syndrome caused by verotoxin-producing Escherichia coli intestinal infection}; Cooper JG et al.; Enteric infections with verotoxin-producing Escherichia coli can progress to the haemolytic-uraemic syndrome . Several reports suggest that the incidence of verotoxin-producing E coli infections is increasing in the USA and Europe . Small epidemics of haemolytic-uraemic syndrome are usually traced to the ingestion of beef or dairy products . Epidemics of diarrhoea-associated haemolytic-uraemic syndrome have not yet been reported in Norway . We describe, for the first time in Norway, a sporadic case of haemolytic-uraemic syndrome that was associated with a verotoxin infection . Despite several life-threatening relapses the patient eventually made a good recovery after treatment with supportive therapy, plasma exchange, plasma infusions, corticosteroids, vincristine and ciprofloxacin . The authors stress the importance of continuing with intensive supportive therapy even when the prognosis seems hopeless.

Clin Infect Dis, 1994 Nov, 19(5), 866 - 70
Invasive otitis externa due to Aspergillus species: case report and review; Gordon G et al.; Aspergillus flavus, an unusual cause of malignant external otitis, was identified in pure culture of tissue from two patients in which histologic examinations demonstrated branching septate hyphae invading the temporal bone . Both patients presented with protracted external ear pain . Multiple attempts at treatment with topical agents (polymyxin B sulfate-neomycin sulfate-hydrocortisone), oral agents (cephalexin and ciprofloxacin), and parenteral agents (ceftazidime and tobramycin) were unsuccessful before definitive diagnosis was made . Treatment with amphotericin B, followed by a more protracted course of itraconazole, resulted in an apparent cure for these patients . Follow-up examination at 15 months after the discontinuation of therapy with itraconazole demonstrated no recurrence of infection . Previously reported cases have predominantly involved immunocompromised persons, and these cases are summarized.

J Infect, 1994 Nov, 29(3), 327 - 30
Stomatococcus mucilaginosus lower respiratory tract infection in a patient with AIDS; Cunniffe JG et al.; We describe a case of recurrent Stomatococcus mucilaginosus lower respiratory tract infection in a patient with AIDS . Apart from S . mucilaginosus no other pathogens were found to account for infection . There was a rapid response to rifampicin, the organism being resistant to penicillin, co-trimoxazole and ciprofloxacin . Infections caused by this organism are increasingly described, but there are few reports of lower respiratory tract infection.

Diagn Microbiol Infect Dis, 1994 Nov, 20(3), 167 - 70
Preliminary interpretive criteria for in vitro susceptibility testing of CP-99219 by dilution and disk diffusion methods; Jones RN; CP-99219 is a novel 7-{3-azabicyclo (3.1.0) hexyl} quinolone that possesses activity against a wide variety of aerobic and anaerobic pathogens . The disk diffusion test results (5-micrograms CP-99219 disks) were compared with CP-99219 minimum inhibitory concentrations (MICs) using 445 contemporary clinical isolates, including 210 strains that were resistant to ciprofloxacin (MICs, > or = 4 micrograms/ml) . A high correlation was observed between methods (r = 0.97), and the proposed conservative zone diameter interpretive criteria were selected primarily from the regression equation as follows: susceptible at > or = 15 mm (< or = 2 micrograms/ml, preferred) and resistant at < or = 10 mm (> or = 8 micrograms/ml); or susceptible at > or = 19 mm (< or = 1 microgram/ml) and resistant at < or = 14 mm (> or = 4 micrograms/ml) . Using these criteria, the occurrence of false-resistant and false-susceptible disk diffusion test results should remain rare (< or = 1.5%).

Cornea, 1994 Nov, 13(6), 496 - 9
Tear concentrations of topically applied ciprofloxacin; Limberg M et al.; An open-label study of 20 normal, healthy volunteers was conducted to determine the tear concentrations after topical ocular application of ciprofloxacin 0.3% ophthalmic solution (Ciloxan) . Tear samples were collected on Schirmer tear strips at 30 min, 2, 3, and 4 h, and were analyzed for ciprofloxacin using reverse-phase high-performance liquid chromatography . The results of this study showed the mean concentration, 4 h after dosing of ciprofloxacin, to be 16.0 micrograms/ml with 95% confidence limits of 8.15 and 23.79 . It is concluded that concentrations of ciprofloxacin in tears were significantly greater than the minimum inhibitory concentrations for 90% of strains tested commonly reported for a majority of potential pathogens (i.e., < or = 2 micrograms/ml) 4 h after a single application of ciprofloxacin ophthalmic solution 0.3%.

J Antimicrob Chemother, 1994 Nov, 34(5), 737 - 46
Quantitation of GABAA receptor inhibition required for quinolone-induced convulsions in mice; Tsutomi Y et al.; We quantified the amount of inhibition of gamma-aminobutyric acid (GABA)A receptor binding required for the onset of convulsions induced by ciprofloxacin in combination with biphenylacetic acid (BPAA) in mice . In fasting mice iv ciprofloxacin given 30 min after oral BPAA (50 mg/kg) induced convulsions at doses of 40 mg/kg or above . In contrast, ofloxacin caused no convulsions even at 100 mg/kg, the highest dose tested . When mice received 40 mg/kg of ciprofloxacin or ofloxacin, maximal brain concentrations of each quinolone at 30 min were 0.37 or 1.97 micrograms/g, respectively . These brain concentrations of ciprofloxacin and ofloxacin were not affected by combination with BPAA . In the presence of ciprofloxacin and BPAA (at brain tissue concentrations which induced convulsions), the binding of 3H-muscimol to GABAA receptor sites was inhibited by approximately 30% . Using results from a similar binding study, an impracticable iv dose of ofloxacin (500 mg/kg) was estimated to be required to inhibit GABAA receptor binding by 30%, and therefore to induce similar convulsions to those seen with ciprofloxacin at a dose of 40 mg/kg . These results may indicate that epileptic convulsions occur when ciprofloxacin and BPAA interact with each other to antagonize at least 30% of GABAA receptor binding in mice, and provide evidence for a significant role of GABAA receptor inhibition in the occurrence of quinolone-induced convulsions.

Clin Ther, 1994 Nov-Dec, 16(6), 1068 - 77
Rate of exposure to theophylline-drug interactions; Pashko S et al.; Many drugs have been shown to interact adversely with theophylline, including ciprofloxacin, verapamil, and cimetidine . These drug interactions may have serious results such as seizures, circulatory failure, and respiratory arrest, which may require hospitalization . Thus interactions should be prevented . This study was conducted to help understand the degree to which patients taking theophylline are exposed to the potential risks of theophylline toxicity . Detailed diagnostic, demographic, and health care utilization data were obtained from the Pennsylvania Medicaid Management Information System computer files on patients who filled at least one prescription for any theophylline-containing drug between October 1, 1991, and December 31, 1992, and whose prescriptions for theophylline extended into 1992 . The outcome measure of interest in this analysis was the rate at which patients were exposed to potential theophylline interactions, defined as the percentage of time that a patient was taking theophylline that he or she was also prescribed another drug known to interact adversely with theophylline . A total of 17,933 patients met the study criteria . On average, patients included in the analysis received theophylline for 121.3 out of 365 days in 1992 . When the theophylline-interacting drugs were examined in the aggregate, 6619 patients (36.9%) were prescribed at least one of the drugs concomitantly with theophylline, for an average duration of 70.4 days of exposure . The overall rate of exposure to potential theophylline-drug interactions was 17.8% . These findings indicate that patients taking theophylline are exposed to adversely interacting drugs a significant proportion of the time that they are receiving theophylline . Clinicians should be made aware of this risk so that they may prescribe safer treatments that avoid this problem.

Drug Ther Bull, 1994 Oct 20, 32(10), 78 - 9
Fluoroquinolones for the eye; Effects of continuous exposure to ciprofloxacin on the outer membrane of P . aeruginosa; Chair of Clinical Microbiology I, Faculty of Medicine and Surgery, La Sapienza University of Rome, ItalyThe present work evaluated the effect of ciprofloxacin on the outer membrane proteins (OMPs), lipopolysaccharide (LPS) and the variation of minimal inhibitory concentrations (M.I.C.) of three P . aeruginosa strains after using 1/2 and 1/16 sub-M.I.C . drug doses for five days . Ciprofloxacin significantly modified the M.I.C . values . After contact with sub-M.I.C . drug doses two strains showed a decreased expression of a band migrating at 46 Kd, i.e . in the region of protein D that some authors claim is involved in quinolone diffusion . No major alteration of LPS structure was observed.

Pharm Res, 1994 Oct, 11(10), 1424 - 8
Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition; Davis JD et al.; Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics . The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33-46) at steady state plasma concentrations of 0-33 mg.l-1, achieved by supplementing an intravenous bolus dose with a constant rate infusion . The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg.kg-1 were described using a competitive inhibition model . The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone . The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat . The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change . These values were 4.7 microM and 16.3 microM for ENOX and CIPRO, respectively . Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO . The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were 'designed out.'

Antimicrob Agents Chemother, 1994 Oct, 38(10), 2469 - 70
In vitro activities of enoxacin, enrofloxacin, sparfloxacin, and ciprofloxacin against Escherichia coli strains isolated from diarrheic lambs and kids; Cid D et al.; The in vitro activities of four fluoroquinolone compounds were tested against 92 Escherichia coli strains of ovine and caprine origin under aerobic and anaerobic incubation conditions . The four fluoroquinolones proved to be highly effective against the E . coli isolates tested . When bacteria were cultured anaerobically, at least fourfold increases in the MICs of enoxacin for the strains occurred and no detectable changes in enrofloxacin, sparfloxacin, and ciprofloxacin MICs occurred.

Vet Hum Toxicol, 1994 Oct, 36(5), 476 - 7
The use of ciprofloxacin in veterinary proprietary products of enrofloxacin; Sumano LH et al.; A 3-mo chemical surveillance of 5 proprietary products of enrofloxacin for veterinary use was carried out . In all, 50 samples were analyzed by thin-layer chromatography and UV-Vis spectroscopy . Only the original brand of enrofloxacin (BAYTRIL) contained 5% of the drug while the 40 samples from the other 4 products contained 7.5% ciprofloxacin . A word of caution is given for the indiscriminate use of fluoroquinolones in veterinary medicine.

Med Clin (Barc), 1994 Sep 10, 103(7), 264 - 6
{Tendinitis due to fluoroquinolones . Description of 2 cases}; Hernandez MV et al.; Two patients with tendinitis by ciprofloxacin are described . In both patients isolated involvement of the Aquilles tendon was produced . The symptoms initiated at 2 to 4 weeks of the beginning of treatment . The two patients had undergone chemotherapy and bone marrow transplantation due to chronic myeloid leukemia and acute promyelocytic leukemia, respectively with no data on recurrence of leukemia being obtained at the time of the tendinitis . Suppression of ciprofloxacin achieved disappearance of the symptomatology.

An Med Interna, 1994 Sep, 11(9), 442 - 4
{Angioimmunoblastic lymphadenopathy . Apropos a case with unusual clinical manifestations and evolution to T-cell lymphoma}; de la Torre Lima FJ et al.; We present the case of a 67-years-old patient which, after treatment with ciprofloxacin, developed fever, exanthema, arthralgias, polyadenopathies, hepatosplenomegaly, autoimmune hemolytic anemia, hypergammaglobulinemia and severe inversion of the CD4/CD8 ratio . Latter, he developed ischemic signs in several locations (splenic and cerebral infarcts), as well as polyneuropathy and inflammatory myopathy . The diagnosis of angioimmunoblastic lymphadenopathy was established through ganglionary biopsy . The patient improved initially with the administration of corticoids, but in a few months, he developed pleomorphic T lymphoma with quick fatal evolution . We discuss the rarity of some of the clinical and laboratory manifestations in this patient and we comment on the association of ciprofloxacin and the angioimmunoblastic lymphadenopathy, which has never been previously described in the international literature.

J Antimicrob Chemother, 1994 Sep, 34(3), 383 - 90
Effect of newer quinolones on the extra- and intra-cellular chemiluminescence response of human polymorphonuclear leucocytes; Aoki M et al.; The direct effect of four quinolones on the intracellular production and extracellular release of reactive oxygen species was investigated in vitro using a chemiluminescence (CL) assay . Polymorphonuclear leucocytes (PMNs) were obtained from healthy volunteers and exposed for 10 min at 37 degrees C to 1.6, 6.25 and 25 mg/L ofloxacin, ciprofloxacin, sparfloxacin and temafloxacin . The luminol-dependent CL response of the PMNs was then measured for 30 min following stimulation with nonopsonized zymosan or phorbol myristate acetate (PMA) . The intracellular CL response was also measured for 30 min during phagocytosis of lumispheres . The integrated CL was calculated and compared for cells which were incubated with the antibiotic and unincubated controls . Preincubation with ofloxacin resulted in increased zymosan and PMA-induced, luminol-dependent CL . Similar increases were observed for ciprofloxacin except that 25 mg/L decreased the PMA-induced, luminol dependent CL . Preexposure to ofloxacin and ciprofloxacin did not affect lumisphere-induced CL significantly, although there was a tendency for this to decrease after exposure to ciprofloxacin . In contrast sparfloxacin and temafloxacin caused progressive decreases in zymosan and PMA-induced, luminol-dependent PMN CL which reached statistical significance at the higher concentrations . The same pattern was observed in the experiments using lumispheres . These findings indicate that these quinolones modulate the oxygen metabolism of PMNs and that this effect varies with the individual drug.

Antimicrob Agents Chemother, 1994 Sep, 38(9), 2187 - 90
Effect of bismuth subsalicylate on ciprofloxacin bioavailability; Rambout L et al.; A single oral dose of 528 mg of bismuth subsalicylate (30 ml of Pepto-Bismol) had no significant effect on the plasma pharmacokinetics of a single oral dose of 750 mg of ciprofloxacin administered to 12 healthy volunteers (six men and six women) . These results suggest that ciprofloxacin bioavailability will not be significantly decreased by single doses of bismuth subsalicylate when the two medications are administered simultaneously.

Antimicrob Agents Chemother, 1994 Sep, 38(9), 2101 - 5
Effect of enteral feeding with ensure on oral bioavailabilities of ofloxacin and ciprofloxacin; Mueller BA et al.; The relative oral bioavailabilities of ciprofloxacin and ofloxacin when they were coadministered with water or an enteral feeding product (Ensure) were assessed in 13 healthy volunteers . The area under the concentration time curve from time zero to infinity and the maximum concentration of drug in serum for both drugs were reduced by Ensure in comparison with those by water (P < 0.01) . However, Ensure reduced the percent relative bioavailability of ciprofloxacin (72% +/- 14%; range, 52 to 96%) significantly more than ofloxacin (90% +/- 8.3%; range, 74 to 105%) (P < 0.005) . Coadministration of Ensure significantly diminished ciprofloxacin and ofloxacin absorption, but ciprofloxacin absorption was reduced significantly more than ofloxacin absorption.

Am J Vet Res, 1994 Sep, 55(9), 1313 - 8
Placental transfer of enrofloxacin and ciprofloxacin in rabbits; Aramayona JJ et al.; Placental transfer of enrofloxacin and ciprofloxacin was evaluated, using a rabbit in situ perfusion model . A two-step infusion program was carried out to obtain steady-state maternal plasma concentrations of these drugs . For each compound, the placenta in 5 rabbits was perfused for 200 minutes with Earle's enriched bicarbonate buffer at flow rate of 1.5 ml/min . To assess reliability of the model, most of the determinants of placental transfer (maternal and fetal pH, gas balance, heart status, rectal temperature, and protein binding) were controlled . In addition, the infusion program included administration of antipyrine, a commonly used indicator of placental exchange . Drug concentrations were measured in maternal plasma and perfusate by use of a high-performance liquid chromatographic assay . Plasma protein-binding estimation indicated no differences between the drugs . Placental clearance of the drugs was significantly (P < 0.01) different (0.88 +/- 0.13 ml/min for enrofloxacin and 0.06 +/- 0.02 ml/min for ciprofloxacin) . These values accounted for 81 and 5%, respectively, of the placental clearance found for antipyrine . These results indicate that caution must be taken when enrofloxacin is to be used during pregnancy, and suggest the need to extend this type of experiment to species that can be exposed to these drugs used for therapeutic or prophylactic purposes.

J Chromatogr B Biomed Appl, 1994 Aug 19, 658(2), 341 - 8
Simultaneous determination of enrofloxacin and its primary metabolite ciprofloxacin in bovine milk and plasma by ion-pairing liquid chromatography; Tyczkowska KL et al.; A simple and sensitive high-performance liquid chromatographic method has been developed for the simultaneous determination of enrofloxacin and ciprofloxacin in bovine milk and plasma . Sample preparation consisted of mixing equal volumes of milk or plasma with acetonitrile-0.1 M sodium hydroxide (1:1, v/v), followed by ultrafiltration through 3000 Da molecular mass cut-off filters . Separation of these two fluoroquinolones in milk or plasma ultrafiltrate was accomplished by ion-pairing liquid chromatography using a reversed-phase analytical column eluted with acetonitrile-methanol-water . Ultraviolet absorbance of the column effluent was monitored over the 230-350 nm range with a photodiode-array detector (lambda max 278 nm) . Recoveries of enrofloxacin from bovine milk and plasma were 92-107% and 80-84%, respectively . Recoveries of ciprofloxacin from bovine milk and plasma were 92-105% and 73-75%, respectively . The limit of detection for the two compounds was 5 ng/ml . Enrofloxacin was administered intravenously to a lactating cow at a dose of 2.5 mg/kg . Enrofloxacin was detected in milk within 15 min after injection and the metabolite ciprofloxacin rapidly appeared in plasma and milk . Both enrofloxacin and ciprofloxacin were below the limit of detection (5 ng/ml) by 48 h after drug administration.

Am J Ophthalmol, 1994 Aug 15, 118(2), 145 - 51
Ophthalmic manifestations of Rochalimaea species; Golnik KC et al.; Rochalimaea henselae and R . quintana belong to the order Rickettsiales and are thought to be responsible for trench fever, bacillary angiomatosis, and cat scratch disease . We recently examined four patients with intraocular inflammation of unknown origin . Each patient had either unilateral or bilateral moderate loss of visual acuity ranging from 20/25 to counting fingers . Bilateral intraocular inflammation manifested by anterior and posterior segment cells, retinal lesions, macular exudate, and optic nerve head swelling was present to varying degrees . The R . henselae to R . quintana antibody titers were greater than or equal to 1:256 in each case . Marked improvement in vision occurred after treatment with either oral ciprofloxacin hydrochloride and prednisone or doxycycline hyclate . Rochalimaea species should be considered in the differential diagnosis of intraocular inflammation and inflammatory optic neuropathy . Appropriate treatment may result in marked improvement in visual acuity.

J Clin Pharm Ther, 1994 Aug, 19(4), 261 - 2
Stability of ciprofloxacin in 5% dextrose and normal saline injections; Mathew M et al.; The stability of ciprofloxacin in 5% dextrose and normal saline i.v . admixtures have been determined using a stability-indicating high performance liquid chromatographic assay method reported in the literature . The solutions were stored in plastic bags, a procedure being used in hospitals for in or out-patient therapy . The solutions were stable for at least 3 months when stored at room or refrigerator temperatures . They remained clear throughout the study and their pH values did not change . The expiry date recommended by the manufacturer appears to be very conservative from a chemical viewpoint.

J Clin Pharm Ther, 1994 Aug, 19(4), 257 - 9
Lack of a pharmacokinetic interaction between ciprofloxacin and fenbufen; Kamali F; The possible effects of a three day pretreatment with fenbufen on the pharmacokinetics of a single oral (500 mg) dose of ciprofloxacin were evaluated in a randomized crossover study in a group of eight healthy male volunteers . Fenbufen pretreatment was shown to have no significant effect on ciprofloxacin pharmacokinetics.

Antimicrob Agents Chemother, 1994 Aug, 38(8), 1794 - 802
In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations; Klopman G et al.; The relationship between the structures of quinolones and their anti-Mycobacterium avium activities has been previously derived by using the Multiple Computer-Automated Structure Evaluation program . A number of substructural constraints required to overcome the resistance of most of the strains have been identified . Nineteen new quinolones which qualify under these substructural requirements were identified by the program and subsequently tested . The results show that the substructural attributes identified by the program produced a successful a priori prediction of the anti-M . avium activities of the new quinolones . All 19 quinolones were found to be active, and 4 of them are as active or better than ciprofloxacin . With these new quinolones, the updated multiple computer-automated structure evaluation program structure-activity relationship analysis has helped to uncover additional information about the nature of the substituents at the C5 and C7 positions needed for optimal inhibitory activity . A possible explanation of drug resistance based on the observation of suicide inactivation of bacterial cytochrome P-450 by the cyclopropylamine moiety has also been proposed and is discussed in this report . Furthermore, we confirm the view that the amount of the uncharged form present in a neutral pH solution plays a crucial role in the drug's penetration ability.

Ther Drug Monit, 1994 Aug, 16(4), 427 - 31
Effect of ciprofloxacin on the pharmacokinetics of multiple-dose phenytoin serum concentrations; Job ML et al.; We performed this study to determine if an interaction exists during the co-administration of ciprofloxacin with phenytoin . Seven healthy volunteers received oral phenytoin, 200 mg/day, as a single dose for 10 days . On day 9, phenytoin blood sampling was performed at times 0, 1, 2, 4, 6, 8, 10, 12, and 24 h . On day 10, oral ciprofloxacin, 500 mg, b.i.d . was initiated . On day 14, blood samples were collected as previously described . Pharmacokinetic analysis was performed to determine if there were differences between the area under the concentration time curve (AUC), maximum serum concentration, Cmax, and time of maximum serum concentration, Tmax, of phenytoin before and during co-administration of ciprofloxacin . Four subjects completed the study . Results of the analysis showed no significant differences between AUC, Cmax, and Tmax of phenytoin before and during ciprofloxacin administration . However, one subject showed marked reductions in both AUC and Cmax . Similar reductions in plasma concentrations have also been reported, resulting in breakthrough seizures . In conclusion, ciprofloxacin was not shown to increase phenytoin plasma concentrations or AUC in healthy volunteers . The potential for decreasing plasma phenytoin concentrations may exist and warrants close monitoring of levels when these two agents are given simultaneously.

J Antimicrob Chemother, 1994 Aug, 34 Suppl A, 33 - 42
Biopharmaceutical aspects of anti-infective therapy at the extremes of age; Schaefer HG et al.; Optimal anti-infective therapy at the extremes of age can be supported by the development of appropriate dosage forms . With regard to neonates, infants and children an oral liquid formulation appears to be superior compared with standard formulations such as tablets and capsules, since individualized dosing by body weight or body surface area is more easily achieved . Reformulation of marketed dosage forms, such as crunched tablets or opened capsules, by the hospital pharmacist may result in stability and bioavailability problems and therapeutic failures may be the consequence . With regard to the elderly a reduction in dosing frequency and individualized dosing are important in order to increase compliance . A reduction of dosing frequency can be achieved by oral controlled-release dosage forms, which are designed to release the drug in small amounts at predefined rates . However, to permit ease of swallowing they require a relative small daily dose together with excipients . In addition absorption must occur throughout the entire gastrointestinal tract; this is not the case for several antibiotics . Various advantages and disadvantages of oral liquid and oral controlled-release dosage forms are discussed . In the development of an oral formulation, in addition to a standard tablet a variety of information, such as physico-chemical characteristics, pharmacokinetics and pharmacodynamics must be available . Physico-chemical disadvantages can largely be solved by advanced pharmaceutical concepts, such as the pro-drug approach, complex formation or coprecipitation, which are discussed . Using ciprofloxacin with its long lasting and extremely bitter taste as an example, the pharmaceutical development of an oral liquid formulation and the pharmacokinetic investigations in healthy volunteers are described.

Transplantation, 1994 Jul 15, 58(1), 114 - 6
Transplantation of a hepatitis B surface antigen-positive donor liver into a hepatitis B virus-negative recipient; Gonzalez-Peralta RP et al.; A critically ill, HBV seronegative girl who received a liver from a HBsAg+ donor is described . Despite HBV Ig prophylaxis, she was seropositive for HBsAg shortly after transplantation . Although the postoperative period was complicated, HBV-related problems were not encountered . Liver dysfunction was noted 7 months after transplantation . At that time, she became anti-HBc IgM-positive, with liver histologic findings suggestive of chronic active hepatitis B . The liver function normalized after a reduction of immunosuppressive therapy and introduction of ciprofloxacin . The patient had low level HBV replication during the entire follow-up period (HBV DNA-positive by PCR only) and sequencing of the virus on 4 occasions revealed only wild-type HBV . She subsequently lost serum HBsAg and HBV DNA (even by PCR) and has remained well 2 years after transplantation.

Cancer Res, 1994 Jul 1, 54(13), 3436 - 41
Phase Ib trial of pentoxifylline and ciprofloxacin in patients treated with interleukin-2 and lymphokine-activated killer cell therapy for metastatic renal cell carcinoma; Thompson JA et al.; The dose of interleukin 2 (IL-2) which can be administered to cancer patients is limited largely by a capillary leak syndrome . Pentoxifylline (PTX) is a methylxanthine which reduces IL-2 toxicity in animals . Ciprofloxacin (Cipro) modifies the metabolism of methylxanthines and, when coadministered with PTX, increases levels of PTX and certain of its metabolites . We conducted a phase Ib trial in patients receiving IL-2 and lymphokine-activated killer cell (LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX which could be coadministered with Cipro in this setting . Eighteen patients received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m2/day on days 1-5 and underwent leukapheresis on days 7-9 . LAK cells were infused on days 12-14 . IL-2 was administered at 2 x 10(6) units/m2/day on days 10-20 . Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v . infusion every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o . every 12 h) on days 1-5 and 10-20 . Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical regimen of IL-2/LAK without PTX/Cipro . PTX at 2.5-3.9 mg/kg and Cipro were well tolerated . The maximum tolerated dose of PTX was 3.9 mg/kg . Dose-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible . Two complete, one partial and one minor, responses were observed . Patients treated with 3.9 mg/kg PTX received 95.0% of the planned dose of IL-2 as compared to 72.8% in the control patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients . The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK without apparent loss of therapeutic efficacy . Moreover, PTX/Cipro recipients exhibited less toxicity than historical controls . Therefore, treatment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.

J Antimicrob Chemother, 1994 Jul, 34(1), 7 - 19
The use of fluoroquinolones in neutropenic patients--analysis of adverse effects; Rubinstein E et al.; The fluoroquinolones have been extensively used in the neutropenic patient . When fluoroquinolone monotherapy was used as prophylaxis, frequently for extended periods, the rate of adverse effect of ciprofloxacin (6.9%) ofloxacin (11.6%) and norfloxacin (5.5%) were significantly lower than those of the comparator agents--co-trimoxazole, vancomycin and polymycin . Rash and gastrointestinal upset were the commonest adverse effects associated with the fluoroquinolones . When used as monotherapy for bacterial infections, often intravenously and in high dosages, the cumulative rate of adverse effects caused by the fluoroquinolones (12.6%) was similar to that caused by the comparator agents (10.3%), but significantly higher than reported for non-neutropenic patients (6.4%) and for prophylactic use . The main adverse events were also rashes (15.4%) and gastrointestinal upset (6.1%) . When fluoroquinolones were used as therapy of bacterial infections in combination with other agents, the incidence of adverse events was 14.9%, which was similar to the comparator agents (13.5%) . Adverse events were also similar except that nephrotoxicity was commonest with comparator combinations (4.0%) . The data suggest that fluoroquinolone prophylaxis in neutropenic patients, even for prolonged periods, is safer than the comparator agents, but is associated with more frequent adverse events than in non-neutropenic patients . Fluoroquinolone therapy, frequently with high dosages, is associated with similar rate of adverse events as the comparator agents . When used in combination with the other antibiotics, fluoroquinolones are as safe as the comparator agents.

Ann Pharmacother, 1994 Jul-Aug, 28(7-8), 869 - 72
Concurrent use of foscarnet and ciprofloxacin may increase the propensity for seizures; Fan-Harvard P et al.; OBJECTIVE: To report a possible interaction between foscarnet and ciprofloxacin in two patients with AIDS, cytomegalovirus (CMV) retinitis, and disseminated Mycobacterium avium complex (MAC) infection and to review the available literature related to foscarnet-associated seizures . DATA SOURCE: Case report information was obtained from Medical Service Daily Rounds during the patients' hospitalization and from the patients' medical records . Computerized (MEDLINE) and manual (Index Medicus) search methods were used to obtain English-language literature published between 1980 and 1993 . DATA SYNTHESIS: Foscarnet is a synthetic antiviral agent with activity against herpesviruses and HIV . The incidence of seizures with foscarnet infusion is high, ranging from 13 to 15 percent . Predisposing factors such as renal impairment, electrolyte and metabolic abnormalities, and underlying neurologic disorders have been associated with seizures during foscarnet therapy . We describe two patients with AIDS who developed generalized tonic-clonic seizures while receiving foscarnet and ciprofloxacin for the treatment of CMV retinitis and disseminated MAC infection, respectively . Neither of the patients had any of the aforementioned risk factors for foscarnet-associated seizures . CONCLUSIONS: Concurrent administration of ciprofloxacin, a known epileptogenic agent, and foscarnet may predispose patients to the development of seizures.

Clin Infect Dis, 1994 Jul, 19(1), 42 - 7
Streptomycin and alternative agents for the treatment of tularemia: review of the literature; Enderlin G et al.; Because of the recent lack of availability of streptomycin--currently considered the drug of choice for the treatment of tularemia--we reviewed the literature on alternative drugs that have been used for this purpose . In addition, we reviewed data on the in vitro susceptibility of Francisella tularensis to a wide variety of agents . The rate of cure for streptomycin was 97%, with no relapses . For gentamicin and tetracycline, respectively, the rates of cure were 86% and 88%, the rates of relapse were 6% and 12%, and the rates of failure were 8% and 0 . The duration of therapy with gentamicin and a delay in its initiation may have affected outcome in severe cases . For chloramphenicol and tobramycin, cure rates were 77% and 50%, respectively; relapse rates were 21% and 0; and failure rates were 2% and 33%, respectively . Treatment with imipenem/cilastatin was successful in one case, and that with ciprofloxacin or norfloxacin was successful in six cases; in contrast, therapy with ceftriaxone was ineffective in eight cases . On the basis of this review, we conclude that gentamicin is an acceptable alternative to streptomycin for the treatment of tularemia.

Antimicrob Agents Chemother, 1994 Jun, 38(6), 1356 - 62
Ciprofloxacin and sparfloxacin penetration into human brain tissue and their activity as antagonists of GABAA receptor of rat vagus nerve; Davey PG et al.; Patients undergoing elective surgery for removal of brain tumors, aneurysms, or other vascular malformations were administered a single oral dose of sparfloxacin (400 mg; 16 patients) or ciprofloxacin (750 mg; 5 patients) either 3 to 5 h or 22 to 26 h before surgery . Serum samples were taken from all patients at 0, 1, 3 to 5, 7 to 9, and 22 to 26 h after dosing; an additional serum sample was obtained at 48 h from patients who received sparfloxacin . A single sample of brain tissue was taken from all patients; a sample of cerebrospinal fluid (CSF) uncontaminated with blood was obtained from five patients . Serum and brain tissue samples were assayed by high-pressure liquid chromatography . Drug concentrations in brain tissue exceeded those in CSF by 1.8- to 19.4-fold . Kinetic modeling suggested that peak sparfloxacin concentrations in brain tissue may have occurred later than 3 to 5 h and that actual peak concentrations may therefore have been higher (up to 10 micrograms/g of tissue) . The activities of ciprofloxacin and sparfloxacin as antagonists of the gamma-aminobutyric acid antagonist (GABAA) receptor were measured with the rat vagus nerve preparation . The 50% inhibitory concentration (IC50) of ciprofloxacin was 250 microM (95.25 micrograms/ml), but in the presence of biphenyl acetic acid (BPAA), the IC50 of ciprofloxacin was only 0.6 microM (0.23 microgram/ml) . In contrast, the IC50 of sparfloxacin alone or in the presence of BPAA was > 300 microM (> 100 micrograms/ml) . We conclude that the concentrations of ciprofloxacin and sparfloxacin in brain tissue may exceed serum drug concentrations and cannot be predicted from the concentrations in CSF . Sparfloxacin does not have any activity as a GABA antagonist, either alone or in the presence of BPAA, at the concentrations which are likely to be reached in human brain tissue.

Clin Infect Dis, 1994 Jun, 18(6), 999 - 1001
Mycobacterium chelonae (M . chelonae subspecies chelonae): report of a patient with a sporotrichoid presentation who was successfully treated with clarithromycin and ciprofloxacin; Zahid MA et al.; We describe a sporotrichoid presentation of infection with Mycobacterium chelonae (M . chelonae subspecies chelonae) . The disease occurred in a patient receiving corticosteroid therapy and was cured by the use of clarithromycin and ciprofloxacin.

Eur Neuropsychopharmacol, 1994 Jun, 4(2), 151 - 6
Electrically evoked potentials in the rat hippocampus slice in the presence of aminophylline alone and in combination with quinolones; Dimpfel W et al.; The excitability of brain matter was tested bt electrically evoked field potentials in the CA1 region of the rat hippocampus in vitro . In contrast to the quinolones which only increased the amplitudes of electrically evoked potentials, aminophylline induced spontaneous firing in the pyramidal cell layer without stimulation in addition to its dose-dependent effects on the amplitudes of the evoked potentials . Threshold doses of the quinolones tested (0.25 microM) increased the amplitudes of evoked potentials in the presence of an otherwise ineffective concentration of aminophylline (0.5 microM) to different degrees, ranging from 135.3% for ciprofloxacin to 223.8% for nalidixic acid . The rank order of potency of CNS side effects reported in the literature correlates very well with the increase of the population spike amplitude in the hippocampus slice preparation . This feature could be important during the development of new chemical analogues of quinolones.

Ann Pharmacother, 1994 Jun, 28(6), 714 - 9
Assessment of methods and outcomes: using modified inpatient ciprofloxacin criteria in community-based drug use evaluation; Rovers JP et al.; OBJECTIVE: To determine if published drug use evaluation (DUE) criteria for inpatients could be modified to describe and evaluate drug therapy in outpatients . DESIGN: Retrospective review of drug profiles and diagnostic codes in outpatients included in the Iowa Medicaid Management Information System database . METHODS: Criteria specifying clinical indication, process indicators, complications, and outcomes were modified from existing inpatient DUE criteria for ciprofloxacin . The Iowa Medicaid database provided demographics, drug profiles, and diagnostic codes for outpatients prescribed ciprofloxacin between March 1 and March 15, 1993 . RESULTS: 539 patients were evaluated . Mean (+/- SD) age was 62.1 +/- 23.8 years; 70.9 percent were women, 44.9 percent were nursing home patients who received lower doses (p = 0.04) . Of 146 patients (27.1 percent) with infection-related International Classification of Diseases-Clinical Modification, 9th Revision (ICD-9CM) codes, 43.8 percent did not meet indication for use criteria, 15.8 percent met criteria, and 40.4 percent were equivocal/other . Process indicators in 539 patients revealed that 2.4 percent were < 18 years old and potential interactions existed for theophylline (9.3 percent), iron (9.7 percent), warfarin (4.8 percent), sucralfate (2.2 percent) . Two patients (0.4 percent) received prenatal vitamins . Dosage and duration of therapy could not be linked to disease severity . Complications of therapy were not evaluable . Outcomes were assessed indirectly by using concurrent antibiotic histories . These histories showed that patients received a mean 2.7 +/- 2.4 (median 2, range 1-16) ciprofloxacin prescriptions during the study period . There was frequent concurrent use of antibiotics, and 29 percent of prescriptions were preceded or followed by additional quinolone therapy within 30 days . CONCLUSIONS: Evaluating appropriateness of therapy with this methodology is feasible if validated ICD-9CM codes are reported consistently in sufficient numbers of patients . Low levels of reporting of relevant disease codes require that large numbers of patients be screened to use this method effectively . Descriptive use data are readily obtained . Data obtained by this method indicated several apparent deficiencies in ciprofloxacin therapy.

Am J Ophthalmol, 1994 May 15, 117(5), 657 - 62
Comparative efficacy of topical ciprofloxacin for treating Mycobacterium fortuitum and Mycobacterium chelonae keratitis in an animal model; Lin R et al.; Mycobacterium fortuitum and M . chelonae are the two most common causes of nontuberculous mycobacterial keratitis, and they may be difficult to differentiate at diagnosis . Mycobacterium fortuitum is generally more sensitive to ciprofloxacin in vitro than is M . chelonae . Using a rabbit model, we compared the efficacy of topical ciprofloxacin (3 mg/ml) against M . chelonae keratitis to its efficacy against M . fortuitum keratitis . After four days of therapy, ciprofloxacin significantly reduced the number of both organisms in treated eyes compared to untreated control eyes (both P values < .001) . Mean culture ratios (colony-forming units in treated eye divided by colony-forming units in untreated eye for each rabbit) were used to compare efficacy between groups . When all treated animals were considered, no significant difference was found between groups (P = .13) . When outlier values were excluded, ciprofloxacin was more effective against M . fortuitum than M . chelonae (P = .01) . When treated and untreated eyes were compared after therapy in the M . fortuitum group, ciprofloxacin treatment was associated with a reduction in mean stromal infiltrate area (P = .03) and in the tendency to form satellite lesions (P = .07) . A clinical effect was not observed in the M . chelonae group . Although ciprofloxacin is effective against both organisms, it appears to be less effective against M . chelonae than M . fortuitum in vivo.

Chemotherapy, 1994 May-Jun, 40(3), 209 - 14
Magnetic resonance imaging in children receiving quinolones: no evidence of quinolone-induced arthropathy . A multicenter survey; Danisovicova A et al.; Twenty-nine children with cystic fibrosis (CF) were investigated for quinolone-induced arthropathy . Magnetic resonance imaging (MRI) was performed in 14/14 children treated with ofloxacin or ciprofloxacin and in 10/15 of those never treated with quinolones . The frequency of pathologic MRI findings, concerning cartilage thickness, careful analysis of the cartilage structure, presence of edema, cartilage-bone borderline and the presence of fluid in joints did not show any difference between both groups . Thus the presence of quinolone-induced arthrotoxicity cannot be confirmed in this study.

J Rheumatol, 1994 May, 21(5), 877 - 82
Ureaplasma urealyticum in Reiter's syndrome; Horowitz S et al.; OBJECTIVE . To evaluate the role of Ureaplasma urealyticum (Uu) in the pathogenesis of Reiter's syndrome (RS) . METHODS . Infection with Uu was determined in 31 patients with RS and 28 patients with other arthritides by urethral, cervical and synovial fluid (SF) culture and by measuring anti-Uu serum antibody . Infection with Chlamydia trachomatis was determined by examining SF by a direct immunofluorescence technique, by a polymerase chain reaction and by measuring anti-C . trachomatis serum antibody . The proliferative response of SF and peripheral blood mononuclear cells (PBMC) to Uu antigens in patients with RS was compared to that of a control group . The effect that treatment of 6 patients with RS with ciprofloxacin had on repeated cultures, on titer of anti-Uu antibody and on mononuclear cell reactivity was measured sequentially . RESULTS . The colonization rate of Uu in patients with RS (74%) was significantly greater than in patients with other arthritides (14%) . Genital C . trachomatis isolation and serum anti-C . trachomatis antibody were uncommon in both groups (11 and 13%, respectively) . SF mononuclear cells of the patients with RS proliferated specifically in response to Uu antigens {up to 6.9 stimulation index (SI)}, as did their PBMC (up to 14.5 SI) . In some patients, high anti-Uu antibody titers were measured in the serum . Clinical remission was observed in 4 of 6 patients and correlated with eradication of Uu, decrease in antibody titers and disappearance of mononuclear cell reactivity to Uu antigens . CONCLUSION . Our findings suggest that Uu might be a causative agent or a trigger in the development of sexually acquired RS.

Zhongguo Yao Li Xue Bao, 1994 May, 15(3), 197 - 201
An improved HPLC assay for ciprofloxacin in biological samples; Pei YY et al.; A simple and sensitive high performance liquid chromatographic method was developed for determination of ciprofloxacin (Cip) in 0.1 ml of rabbit and human serum and CSF . Separation of Cip and pipemidic acid (internal standard) was achieved on Nucleosil C18 (4.6 mm x 250 mm) using fluorescence detection with lambda exc 274 nm and lambda emi 418 nm . The mobile phase was composed of acetonitrile and phosphate buffer 10 mmol.L-1 (pH 2.7) containing tetrabutylammonium hydrogen sulfate 5 mmol.L-1 (18:82, vol:vol) and the flow rate was set at 1.0 ml.min-1 . The retention times were 5.9 min for Cip and 4.0 min for pipemidic acid . The inter-day coefficient of variation was < 6.97% (n = 5) and the intra-day coefficient of variation was < 3.33% (n = 5) . The limits of detection were 3 ng.ml-1 serum and 5 ng.ml-1 CSF, (r > or = 0.9996) . Application of this method was demonstrated with simultaneous measurements of concentration-time profiles of Cip in rabbit serum and CSF during iv infusions at constant rates of 0.33, 1.0, and 2.5 mg.kg-1.h-1.

Hinyokika Kiyo, 1994 May, 40(5), 401 - 6
{Concentrations of new quinolone agents in serum and prostate tissue}; Imai K et al.; Twenty five patients with benign prostate hypertrophy were administered ofloxacin (OFLX) simultaneously with norfloxacin (NFLX) in 6 patients, ciprofloxacin (CPFX) in 10, tosfloxacin (TFLX) in 5 and enoxacin (ENX) in 4 patients . The dose of these new quinolones was 100 mg (except 150 mg of TFLX) . Their concentrations in the serum and the prostate tissue were measured by high performance liquid chromatography (HPLC) . The serum concentration of OFLX was significantly higher than that of NFLX, CPFX, TFLX or ENX . The prostate tissue concentration of OFLX was significantly higher than that of CPFX or TFLX . The ratio of tissue versus serum concentration of each new quinolone agent was not significantly different . The high OFLX tissue concentration appeared to be caused by the high serum concentration.

J Toxicol Environ Health, 1994 May, 42(1), 73 - 88
Comparison of lesions induced by intra-articular injections of quinolones and compounds damaging cartilage components in rat femoral condyles; Takada S et al.; Twenty-five microliters of a 2% saline solution of levofloxacin (LVFX) or ciprofloxacin (CPFX) was injected every other day for 2 wk into the knee joint space of CD rats (weighing 62.7-86.7 g) from the age of 3 wk . Early in the course of injection, histologic examination revealed chondrocyte necrosis without marked matrix change in the articular cartilage of the femoral condyles adjacent to the intercondylar groove . After 7 injections, the surface and intermediate zones of the articular cartilage showed extensive necrosis, sometimes with cavity formation in the center of the same portion . Papain completely depleted matrix basophilia in all zones throughout the condyle and caused cartilage necrosis with cavity formation . One injection of iodoacetic acid caused necrosis of almost all chondrocytes over the entire condyle, but chondrocytes sometimes remained alive in the portion where cavity formation was induced by quinolones . Chondroitinase depleted the matrix basophilia, and sometimes produced necrotic areas . DNA synthesis inhibitors n-ethylmaleimide, CPT-11, and etoposide (VP-16) caused chondrocyte necrosis, but never caused cavities in the articular cartilage . The DNA synthesis inhibitors n-ethylmaleimide, CPT-11, and hydroxyurea were administered concurrently with po LVFX administration and significantly increased the incidence of LVFX-induced cavity formation . n-Ethylmaleimide was the most effective of all the inhibitors . The quinolone-induced cavity formation is suggested to be site specific in the articular cartilage of rat femoral condyles . The depletion of matrix proteoglycans and chondrocyte necrosis may be necessary, although insufficient, to produce such lesions . Disruption of the collagen framework is suspected to contribute to their development . Involvement of altered DNA metabolism may play a role in the chondrocyte necrosis that occurs early in the specific sites.

J Chemother, 1994 Apr, 6(2), 102 - 6
Activity of BAY y 3118, a novel 4-quinolone, against Brucella melitensis; Garcia-Rodriguez JA et al.; We have tested the in-vitro activities of BAY y 3118, a new chlorofluoroquinolone, ciprofloxacin, sparfloxacin, streptomycin, tetracycline and rifampin against 59 strains of Brucella melitensis . BAY y 3118 (MIC90 0.12 mg/L) was twice as active as sparfloxacin and tetracycline (MIC90 0.25 mg/L) . The activity of ciprofloxacin, rifampin and streptomycin (MIC90 0.5, 2, and 8 mg/L, respectively) was, respectively, four-, sixteen-, and more than sixty-fold lower than that of BAY y 3118.

J Clin Pharm Ther, 1994 Apr, 19(2), 105 - 9
The influence of ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of temazepam in the young and elderly; Kamali F et al.; The effect of pretreatment with a 4-day course of ciprofloxacin (500 mg twice daily) on the pharmacokinetics and pharmacodynamics of a single oral dose of temazepam (10 mg) was investigated in 12 healthy young and nine elderly patient volunteers in a crossover design study . Temazepam clearance was lower in the elderly than in the young, but this difference was not statistically significant . Ciprofloxacin had no significant effect on temazepam pharmacokinetics or pharmacodynamics in either age group.

J Dermatol Sci, 1994 Apr, 7(2), 130 - 5
Phototoxicity and photoallergenicity of quinolones in guinea pigs; Horio T et al.; Clinical reports indicate that the fluoroquinolone group of antibiotics can induce cutaneous photosensitivity reactions . In the present study, phototoxicity and photoallergenicity of quinolones including nalidixic acid (NA) norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX), ciprofloxacin (CPFX), lomefloxacin (LFLX), and tosufloxacin (TFLX) were experimentally examined in an in vivo system using the guinea pig . Phototoxicity of all quinolones tested was demonstrated after a single, oral administration of the drugs and subsequent exposure to long-wave ultraviolet (UVA) at a dose of 30 J/cm2 . The phototoxic potencies were: ENX, LFLX > OFLX > NA, TFLX > NFLX, CPFX . Photoallergic reaction was also induced to LFLX and NA by pretreatment with cyclophosphamide, an immunoadjuvant . No cross-reactions in photoallergy were observed among quinolones . The photo-ingestion test was positive in photoallergically sensitized animals, while the photopatch test was negative . This is the first report which demonstrated experimentally the photoallergenicity of quinolones . Clinical features of the photosensitivity due to quinolones can be explained by the results of the present experiments.

Pharm Res, 1994 Apr, 11(4), 522 - 7
The effect of temperature and pH on the solubility of quinolone compounds: estimation of heat of fusion; Yu X et al.; Although many reports involving fluoroquinolone agents have been published in the past decades, only a few address preformulation studies . In this paper, we describe the effect of temperature and pH on the aqueous solubility of two typically used quinolones, ciprofloxacin and norfloxacin . We measured the aqueous solubilities over the pH range of 5.5 to 9.5 at temperature of 6, 25, 30, and 40 degrees C . The intrinsic solubilities and the thermodynamic dissociation constants were determined from solubility data and the temperature dependence of the intrinsic solubility was evaluated using van't Hoff and Hildebrand plots . The heat of fusion was determined from these two plots . When the heat of fusion was compared to that measured from differential scanning calorimetry (DSC) studies, we found that the Hildebrand method overestimated, and the van't Hoff equation underestimated, the heat of fusion . From the absolute values of the relative errors, the Hildebrand plot produced the better results . DSC results show that the heat of fusion is 15.41 kcal/mol for ciprofloxacin and 7.88 kcal/mol for norfloxacin.

Antimicrob Agents Chemother, 1994 Apr, 38(4), 901 - 4
Penetration of ciprofloxacin into bronchial secretions from mechanically ventilated patients with nosocomial bronchopneumonia; Saux P et al.; The aim of the study was to evaluate the penetration of ciprofloxacin into bronchial secretions from mechanically ventilated patients with nosocomial bronchopneumonia . For this purpose, in each patient studied, simultaneous serial blood and bronchial secretion samples were obtained over a 12-h period on days 2 and 4 . Eight patients were included in the study . Ciprofloxacin was given at a dose of 200 mg over 30 min by using an automatic pump . Ciprofloxacin was measured by high-performance liquid chromatography . Peak levels of drug in serum were 2.95 +/- 1 mg/liter on day 2 and 2.43 +/- 0.7 mg/liter on day 4 . Peak and trough levels in bronchial secretions were 0.95 +/- 0.51 and 0.21 +/- 0.12 mg/liter, respectively, on day 2 and 0.76 +/- 0.17 and 0.18 +/- 0.14 mg/liter, respectively, on day 4 . The ratios of peak concentrations in bronchial secretions/serum were 0.32 +/- 0.11 and 0.33 +/- 0.06 on days 2 and 4, respectively . The ratios of the area under the concentration-time curve from 0 to 12 h (AUC0-12) for bronchial secretions/those for serum were 0.66 +/- 0.40 and 0.55 +/- 0.30 on days 2 and 4, respectively . A significant positive correlation was found on day 4 between the AUC0-12 for serum and the AUC0-12 for bronchial secretions . No significant correlations were found between peak values in serum and bronchial secretions.

Antimicrob Agents Chemother, 1994 Apr, 38(4), 879 - 82
Limited effects of temafloxacin compared with ciprofloxacin on T-lymphocyte function; Riesbeck K et al.; Temafloxacin increased interleukin-2 production and mRNA levels and enhanced thymidine incorporation in stimulated lymphocyte cultures . Gamma interferon mRNA levels were unaffected . Temafloxacin also stimulated interleukin-2 gene induction, as revealed in a chloramphenicol acetyltransferase reporter gene system . However, temafloxacin exerted significantly weaker effects in these respects than did ciprofloxacin.

Antimicrob Agents Chemother, 1994 Apr, 38(4), 757 - 60
Intestinal elimination of ciprofloxacin in rabbits; Ramon J et al.; The intestinal transepithelial elimination of ciprofloxacin was studied in a rabbit model . Jejunal, ileal, and cecal segments along with their intact blood vessels were isolated and perfused, and their contents were collected over a 120-min period following administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight . The intestinal elimination rates of ciprofloxacin were 0.126 +/- 0.084, 0.235 +/- 0.22, and 0.11 +/- 0.084 micrograms.min-1.cm-2 for the jejunal, ileal, and cecal segments, respectively . The calculated fractions of ciprofloxacin eliminated were 3.3 mg from the jejunum and 13.8 mg from the ileum, representing 19% of the administered dose . Additional amounts of 2.5 to 3.7 mg or 4.9 to 7.3% of the administered dose were eliminated from the cecum . Elimination was probably not due to a passive diffusion process but rather due to an active transepithelial transport . This intestinal elimination pattern of ciprofloxacin may explain the unusual activity of the fluoroquinolones in modifying the intestinal flora.

J Chromatogr B Biomed Appl, 1994 Mar 4, 653(2), 187 - 93
Simultaneous determination of ofloxacin, norfloxacin and ciprofloxacin in human hair by high-performance liquid chromatography and fluorescence detection; Mizuno A et al.; A high-performance liquid chromatographic method for the simultaneous determination of ofloxacin, norfloxacin and ciprofloxacin in human hair is described . A reversed-phase C18 column and a fluorescence detector with switching fluorescence wavelengths were used together with solid-phase extraction of the drugs from hair dissolved in 1 M sodium hydroxide . Reproducibility and linearity studies yielded coefficients of variation of 0.2-2.2, 1.4-3.1 and 1.5-3.4%, and correlation coefficients of 1.000, 0.999 and 0.999 within the concentration range 0.3-100 ng/ml for ofloxacin, norfloxacin and ciprofloxacin, respectively . For validation, hair samples were obtained from six subjects who had been taking one or two of the three fluoroquinolones . Assuming a hair growth-rate of 1 cm per month fluoroquinolones could be detected in the hair section(s) that had grown approximately between the dates of drug administration and hair sampling.

Pharmacotherapy, 1994 Mar-Apr, 14(2), 153 - 61
Assessment of the effects of ciprofloxacin and nalidixic acid on cerebral blood flow and metabolism in healthy subjects by positron emission tomography; Bednarczyk EM et al.; STUDY OBJECTIVES . The mechanism by which the fluorinated quinolones produce central nervous system effects is unknown . Using positron emission tomography (PET), we evaluated the effects of two quinolones on brain blood flow as well as on oxygen and glucose metabolism . These determinations were done in conjunction with ophthalmologic and neuro-ophthalmologic testing . DESIGN . Randomized, double-blind, placebo-controlled, 7-day course of ciprofloxacin 750 mg (C750) or 500 mg (C500) every 12 hours, or nalidixic acid (NA) 1 g every 6 hours . POPULATION . Twenty-four healthy male volunteers, six in each treatment arm . RESULTS . {table: see text} CONCLUSIONS . Compared with baseline values, NA significantly reduced brain glucose uptake, whereas C500, C750, and placebo produced no detectable effect . No compound significantly altered brain blood flow or oxygen metabolism compared with baseline or other treatments . No significant effect on electroretinographic, electro-oculographic, or other neuro-ophthalmologic tests was observed.

Ann Pharmacother, 1994 Mar, 28(3), 313 - 5
Penetration of intravenous and oral ciprofloxacin into sterile and empyemic human pleural fluid; Joseph J et al.; OBJECTIVE: To compare the penetration of oral and intravenously administered ciprofloxacin into infected (empyemic) and noninfected (sterile) human pleural fluid . DESIGN: Eleven men and 5 women (aged 29-76) were consecutively selected from adult patients referred to the respiratory unit for pleural effusion . In this open-label, prospective trial, 13 patients with sterile pleural effusions were nonrandomly assigned to receive either ciprofloxacin 200 mg (single intravenous dose), 750 mg (single oral dose), or 750 mg (two oral doses per day for 3 days); 3 patients with infected pleural effusions received 750 mg oral doses for 10 days . Simultaneous pleural fluid and venous blood specimens were drawn over 5 hours after single dose or when steady-state was attained, and ciprofloxacin concentrations were measured by HPLC . RESULTS: Pleural fluid concentrations of ciprofloxacin equaled plasma concentrations 1.5 hours after 200 mg was given intravenously and the pleural/plasma ratio remained > or = 0.9 for 4 hours . After a single 750-mg oral dose, pleural ciprofloxacin concentrations rose from 0 to 1.4 micrograms/mL over 5 hours with the highest pleural fluid/plasma ratio (0.7) at 5 hours . Average steady-state ciprofloxacin concentrations in sterile pleural fluid after 750 mg administered twice daily for 3 days, ranged between 1.1 and 1.8 micrograms/mL with ratios between 0.3 and 0.9 over 4 hours . In empyemic pleural fluid at the same dosage, average steady-state ciprofloxacin concentrations ranged between 1.9 and 3.4 micrograms/mL with ratios between 1.0 and 2.0 over 5 hours . CONCLUSIONS: Oral ciprofloxacin penetrates into sterile and empyemic pleural fluid with concentrations 30-90 percent and 100-200 percent of plasma concentrations, respectively.

Gen Pharmacol, 1994 Mar, 25(2), 369 - 79
Effects of some quinolones on imipenem-induced seizures in DBA/2 mice; De Sarro A et al.; 1 . The behavioural and convulsant effects of imipenem, a carbapenem derivative, were studied after i.p . administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures and in Swiss mice . 2 . It was found that DBA/2 mice were more susceptible to seizures induced by imipenem than Swiss mice . 3 . The proconvulsant effects of some quinolones were also evaluated in DBA/2 mice on seizures evoked by means of i.p . administration of imipenem . The present study demonstrated that the order of proconvulsant activity in our epileptic model was pefloxacin > enoxacin > ofloxacin > nalidixic acid > rufloxacin > norfloxacin > ciprofloxacin > cinoxacin > temafloxacin . 4 . The relationship between the chemical structure and the proconvulsant activity of quinolone derivatives was studied . The relationship between the lipophilicity and the proconvulsant activity was also investigated . 5 . Although the main mechanism for seizure potentiation cannot be easily determined potential drug interactions exist . It has been reported that imipenem and quinolones are all believed to increase excitation of the central nervous system by inhibition of GABA binding to receptors . 6 . A slow clearance from the central nervous system and from the kidney may also occur following the concomitant administration of some quinolones and imipenem.

Immunopharmacology, 1994 Mar-Apr, 27(2), 155 - 64
Increased interleukin 2 transcription in murine lymphocytes by ciprofloxacin; Riesbeck K et al.; The fluoroquinolone antibiotic, ciprofloxacin (cipro), induces hyperproduction of interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) in stimulated human peripheral blood lymphocytes . In this investigation an enhanced and prolonged IL-2 and IL-2 mRNA response was also detected in both stimulated (T cell mitogens or alloantigens) murine splenocytes and in the stimulated murine T cell line EL-4 in the presence of ciprofloxacin (5-80 micrograms/ml) as compared to control cells without antibiotics . However, in contrast to human lymphocytes, IFN-gamma production was inhibited and IFN-gamma mRNA levels were unaffected at 24 h and only slightly upregulated at 48 and 72 h of culture in murine splenocytes incubated with cipro (20 micrograms/ml) . EL-4 cells were transfected with a plasmid containing the IL-2 promoter and enhancer region linked to the chloramphenicol acetyltransferase (CAT) reporter gene . Analysis of CAT activity revealed that cipro enhanced IL-2 gene induction . In addition, EL-4 cells incubated with ciprofloxacin showed an early peak and more activated nuclear factor of activated T cells (NFAT-1) as compared to control cells without antibiotics . Cipro did not affect the nuclear transcription factors AP-1 or NFIL-2A . Taken together, cipro inhibited IFN-gamma synthesis, but enhanced IL-2 production in murine lymphocytes by means of influencing NFAT-1 and causing an increased IL-2 transcription.

Am J Hosp Pharm, 1994 Feb 1, 51(3), 373 - 7
Stability of ciprofloxacin injection in peritoneal dialysis solutions; Kane MP et al.; The stability of ciprofloxacin 25 mg/L in peritoneal dialysis solutions containing 1.5% and 4.25% dextrose after storage at 4 degrees C for two weeks, 25 degrees C for one week, or 37 degrees C for two days was evaluated . Ciprofloxacin 50 mg was added to 18 2-L bags of peritoneal dialysis solutions, nine containing 1.5% dextrose and nine containing 4.25% dextrose . Three bags of each dialysis solution were stored at 4 degrees C for 14 days, 25 degrees C for 7 days, and 37 degrees C for 2 days . Samples were drawn from each bag, and ciprofloxacin concentrations were measured by high-performance liquid chromatography . Stability was defined as less than 10% decrease from initial concentration . In the solution containing 1.5% dextrose, 87.2% of the ciprofloxacin remained after 14 days of storage at 4 degrees C, 93.4% remained after 7 days of storage at 25 degrees C, and 95.2% remained after 2 days of storage at 37 degrees C . In the solution containing 4.25% dextrose, 89.0% of the ciprofloxacin remained after 14 days of storage at 4 degrees C, 93.7% remained after 7 days of storage at 25 degrees C, and 97.8% remained after 2 days of storage at 37 degrees C . In peritoneal dialysis solutions containing 1.5% and 4.25% dextrose, ciprofloxacin was stable for seven days at 25 degrees C and for 48 hours at 37 degrees C . Ciprofloxacin concentrations after two weeks at 4 degrees C were below 90% of initial concentration.

Diagn Microbiol Infect Dis, 1994 Feb, 18(2), 125 - 7
Interpretive criteria for DU-6859a disk diffusion tests using 5-micrograms disks; Jones RN et al.; In vitro disk diffusion test interpretive criteria were developed for DU-6859a, a new difluorinated quinolone, using a 5-micrograms disk . Included in the 494 organisms tested were 84 (17%) ciprofloxacin-resistant > or = 4 micrograms/ml) clinical isolates . The following interpretive criteria were proposed for two possible susceptible breakpoint minimum inhibitory concentrations: > or = 16 mm (< or = 2 micrograms/ml) = susceptible and < or = 12 mm (> or = 8 micrograms/ml) = resistant and; > or = 19 mm (< or = 1 microgram/ml) = susceptible and < or = 15 mm (> or = 4 micrograms/ml) = resistant . These criteria demonstrated > or = 97% absolute interpretive agreement between test methods with no major (false resistant) or very major (false susceptible) errors.

J Pharm Biomed Anal, 1994 Feb, 12(2), 157 - 64
Dissociation and complexation of fluoroquinolone analogues; Lee DS et al.; The dissociation and the complexation behaviours of four fluoroquinolone antibiotics have been studied . The acid dissociation constants of ciprofloxacin, enoxacin, norfloxacin and ofloxacin were determined by conventional potentiometric and conductometric techniques . Increasing the Hammett substituent constant, the pKa values were decreased . The absorption of fluoroquinolones in the intestinal tract are probably transported by pH-dependent mechanisms . Formation constants of the iron(III) complexes (1:1) of the fluoroquinolone analogues were determined by spectrophotometry . The optimum pH for complexation was 3.80.

Gut, 1994 Jan, 35(1), 19 - 22
Evidence for the essential role of Helicobacter pylori in gastric ulcer disease; Labenz J et al.; Helicobacter pylori (H pylori) eradication heals chronic active type B gastritis and dramatically changes the natural history of duodenal ulcer disease . There are few data concerning the role of anti-H pylori treatment in gastric ulcer disease . A total of 83 patients presenting with H pylori positive active gastric ulcer disease were treated with omeprazole and antibiotics (amoxicillin, ciprofloxacin, roxithromycin) in seven different clinical protocols, each of which included the attempt to eradicate H pylori infection and to evaluate the post-therapeutic course of ulcer disease . The overall proportion of H pylori eradication was 67.9% (53 of 78 patients available for follow up) . Best results were obtained with two week treatment regimens comprising omeprazole 20 mg twice daily and amoxicillin 500 mg four times a day or 1000 mg twice daily (eradication > 80%) . Eradication of H pylori speeds up ulcer healing, with a six week healing rate of 84.9% compared with 60% in patients with persistent H pylori infection (p = 0.0148) . In a subgroup of 11 patients with refractory ulcers, H pylori eradication (n = 10) was associated with ulcer healing on continued acid suppression in nine cases . One male patient with chronic antral ulcer did not respond to treatment within the next six months (H pylori and ulcer persistence), and in one female patient a resistant body ulcer was identified as gastric lymphoma . Fifty patients with healed ulcers were followed up for one year . Patients with (n = 32) and without (n = 18) bacterial eradication had similar demographic and clinical characteristics . H pylori eradication was associated with a statistically significant reduction of ulcer recurrences (3.1 v 55.6%, p<0.001) . This study concludes that H pylori eradication considerably changes the natural history of H pylori associated gastric ulcer disease . In addition, H pylori eradication speeds up ulcers healing and is associated with healing of previously refractory ulcers . Thus, treatment aimed at bacterial eradication should be considered in all patients with gastric ulcers severe enough to contemplate further treatment options.

J Infect Dis, 1994 Jan, 169(1), 218 - 21
The intestinal elimination of ciprofloxacin in the rat; Rubinstein E et al.; The transepithelial intestinal elimination of ciprofloxacin was studied in a rat model . Two jejunal and one ileal segment, along with their intact blood supplies, were isolated and continuously perfused . Following a single parenteral administration of 25 mg/kg ciprofloxacin, the drug in amounts of 1.97 +/- 0.70, 1.88 +/- 0.99, and 1.44 +/- 0.77 micrograms/cm2 of mucosal surface was recovered over 90 min from the proximal and distal jejunal loops and the ileal loop, respectively, reaching a calculated fraction of 6%-7% of the dose eliminated in the entire small intestine . The rate of intestinal elimination related linearly to the parenteral dose . In the proximal jejunum, however, doses > 25 mg/kg were not accompanied by a concomitant increase in the eliminated fraction, suggesting a saturable transport process . Parenterally administered probenecid, amoxicillin, and nifedipine and changes ranging from 6.0 to 8.5 in the pH of the perfusates did not alter transepithelial elimination . This pathway of elimination of ciprofloxacin may play an important role in curing intestinal infections.

Ann Pharmacother, 1994 Jan, 28(1), 93 - 6
Does ciprofloxacin interact with cyclosporine?
Hoey LL, Lake KD.
OBJECTIVE: To provide the reader with a review of the literature that evaluates whether a pharmacokinetic or pharmacodynamic drug interaction exists between ciprofloxacin and cyclosporine . DATA SOURCES: A MEDLINE search was used to identify pertinent review articles, pharmacokinetic studies, and case reports . STUDY SELECTION: As both pharmacokinetic trials and case reports were few in number, all available sources were reviewed . DATA EXTRACTION: A few case reports were reviewed; however, data were extracted primarily from prospective human studies involving cyclosporine pharmacokinetic profiles . DATA SYNTHESIS: Ciprofloxacin has been reported to interact with cyclosporine during concomitant use through an interaction with the cytochrome P-450 system or by additive nephrotoxicity . Because ciprofloxacin may be used to treat a variety of infections in transplant recipients who receive cyclosporine, it is important to determine whether an interaction exists . Although cyclosporine is known to cause nephrotoxicity, only a few reports of ciprofloxacin-induced acute renal failure exist, all involving an immune-mediated interstitial nephritis . Four case reports have suggested a possible pharmacokinetic or pharmacodynamic drug interaction between cyclosporine and ciprofloxacin; however, many pharmacokinetic studies have refuted these reports . Several studies performing cyclosporine pharmacokinetic profiles have documented no increased cyclosporine concentrations, thus supporting the premise that ciprofloxacin does not interact with cyclosporine . CONCLUSIONS: Controlled studies involving cyclosporine pharmacokinetic profiles do not support a pharmacokinetic or pharmacodynamic drug interaction between ciprofloxacin and cyclosporine . Although anecdotal case reports have suggested synergistic nephrotoxicity, no clear correlation can be made . Based on our review of the literature, it can be concluded that cyclosporine and ciprofloxacin may be used together safely at the recommended dosages without increased cyclosporine monitoring.

Eur J Clin Pharmacol, 1994, 47(1), 71 - 4
No influence of ciprofloxacin on ethanol disposition . A pharmacokinetic-pharmacodynamic interaction study; Kamali F; The influence of pretreatment with a three day course of ciprofloxacin (500 mg twice daily) on a single oral dose of ethanol (30 g) was investigated in 12 healthy male volunteers in a double blind placebo controlled study . Pretreatment with ciprofloxacin was shown to have no significant effect on ethanol AUC (736 mg.l-1 h placebo; 734 mg.l-1 h ciprofloxacin), Cmax (466 mg.l-1 placebo; 483 mg.l-1 ciprofloxacin) tmax (0.6 h placebo; 0.5 h ciprofloxacin) or the elimination rate (134 mg.l-1 h-1 placebo; 133 mg.l-1 h-1 ciprofloxacin) . The effect of ciprofloxacin on ethanol pharmacodynamics was measured by the use of psychomotor tests, such as the critical flicker fusion threshold, choice reaction time, pursuit rotor, tapping rate, digit symbol substitution and digit span . Subjective feelings of concentration, vigilance and relaxation were also measured using visual analogue scales . Pretreatment with ciprofloxacin was found to have no significant effect on any of these tests, compared to placebo.

Clin Oncol (R Coll Radiol), 1994, 6(4), 232 - 6
Chemotherapy for germ cell tumours: prophylactic ciprofloxacin reduces the incidence of neutropenic fever; Counsell R et al.; To assess the value of prophylactic ciprofloxacin in reducing the incidence of neutropenic fever in men receiving intensive chemotherapy for germ cell tumours, we reviewed the case notes of 88 consecutive patients treated between January 1986 and December 1992 . Nadir blood counts were performed in all patients on day 14 . From 1989, prophylactic ciprofloxacin 250 mg b.d . was started when the neutrophil count was less than 1 x 10(9)/l and then prescribed for all subsequent courses of chemotherapy from day 7 to day 21 . In total, 88 men received 429 courses of chemotherapy . Prophylactic ciprofloxacin was prescribed for 168 courses . This was associated with a trend towards reducing the risk of admission per course of chemotherapy from 8% (20/261) to 4% (6/168) (P = 0.08) . WHO grade 3/4 neutropenia (< 1 x 10(9)/l) was documented for 240 (56%) courses of chemotherapy . The incidence of fever in these patients was significantly reduced from 15% (20/131) to 5% (6/109) (P = 0.02) with prophylactic ciprofloxacin . Two patients, one of whom had received prophylactic ciprofloxacin, died of chest infection confirmed on post-mortem . The results of this non-randomized, retrospective study suggest that prophylactic ciprofloxacin 250 mg b.d . is effective in reducing the incidence of fever complicating neutropenia during chemotherapy for germ cell tumours . To be cost effective, it should be given only to neutropenic patients.

Proc Annu Symp Comput Appl Med Care . 1994;:836-40.
A new knowledge structure for drug-drug interactions; Kuperman GJ et al.; We developed a program to automatically screen patients' medication profiles for pairs of interacting drugs . Since some drug-drug interactions are indicated by changes in physiological parameters (e.g., ciprofloxacin and theophylline leading to an elevation of theophylline levels), the program considered the patients' relevant laboratory parameters prior to generating the alerts . We developed an editor to facilitate maintenance of the knowledge base . We evaluated the program for 3 weeks in two satellite pharmacies . The program reported 160 alerts of which 5 resulted in a change in the patients' therapies (one per 500 patient-days of care) . These five interactions were potentially very serious . An additional 3 alerts led to changes in medication administration times . Subjectively, the program is well received and continues to be in routine clinical use.

Acta Clin Belg, 1994, 49(3-4), 173 - 6
Ciprofloxacin-induced hypersensitivity vasculitis; Beuselinck B et al.; We describe a patient in whom cutaneous vasculitis appeared after 4 days of ciprofloxacin administration . On clinical examination, papular and purpuric lesions were limited to the left axillary zone of the thorax . Skin biopsy did not show the classic leukocytoclastic image but rather a mononuclear infiltrate of the vessel walls . Except a mild increase in inflammatory parameters, there were neither autoantibodies nor biological abnormalities, and the complement level was normal . These findings suggest that ciprofloxacin-induced vasculitis displays histopathological and serologic heterogeneity.

Int J Tissue React, 1994, 16(3), 105 - 12
Effect of levofloxacin and ciprofloxacin injection on permeability of the tail vein in mice and skin microvasculature in rats; Yoshida M et al.; We examined the effects of levofloxacin (LVFX) and ciprofloxacin (CPFX) on the permeability of the tail vein in mice and skin microvasculature in rats after a single intravenous and intracutaneous injection, respectively, with 125I-human serum albumin . In addition, the effect of an H1 histamine antagonist, diphenhydramine, on the hyperpermeability induced by quinolone injections was examined, and the injections were also performed into the tail vein of WBB6F1 (mast cell-deficient) mice . LVFX and CPFX significantly increased the permeability of the mouse tail vein at injection concentrations of 0.2% and 0.05% of more, respectively, and both quinolones increased the permeability of rat skin microvasculature by 0.5% or more . Diphenhydramine concomitantly injected with quinolones completely blocked the hyperpermeability induced by LVFX and CPFX at 0.5% in the mouse tail vein and rat skin microvasculature . Neither quinolone increased the tail vein permeability in WBB6F1 mice . These results suggest that LVFX and CPFX increase vascular permeability through the induction of histamine release from mast cells in rodents.

Tsitologiia, 1994, 36(4), 393 - 400
{The effect of mycoplasmal contamination of cultures of skin fibroblasts from the Indian muntjac and of the subsequent decontamination of the cultures using ciprofloxacin on the karyotypic structure of the cell line}; Polianskaia GG et al.; The karyotypic variability of Indian muntjac skin fibroblast cell line, cultured for 95-168 days after contamination with Acholeplasma laidlawii strain PG-8, has been investigated . The contaminated cultures differ from noncontaminated ones in cell distribution for chromosome number . The noncontaminated cultures have modal number of chromosomes equal to 7 with the main structure variant of the karyotype (SVK) 2+2+1+1+1 . In the contaminated cultures the cell number with 7 chromosomes and the main SVK 2+2+1+1+1 decreased, whereas the cell number with 6 chromosomes increased along with the main SVK 2+2+1+1 resulting from the loss of chromosome Y1 . The treatment of cells with ciprofloxacin for mycoplasma decontamination did not restore the normal cell distribution for chromosome number . The frequency of chromosomal aberrations, mainly dicentrics, due to telomeric associations, increased after 95-168 days of cultivation of contaminated cells . Chromosomes 1 and 2 and their combination are mainly involved in dicentric formations . The treatment of contaminated cells with ciprofloxacin restores the initial frequency of chromosomal aberrations . Chromosomes with altered structures have not been demonstrated . It has been shown that cells became mycoplasma-free after 15 days of treatment with ciprofloxacin . The role of aneuploidy and dicentrics in cell adaptation to culture conditions is discussed.

Tsitologiia, 1994, 36(8), 880 - 7
{A cytogenetic study of the Chinese hamster lung cell line V-79 infected with Mycoplasma arginini and decontaminated using ciprofloxacin}; Polianskaia GG et al.; Karyotypic variability has been studied in a line of the Chinese hamster cells artificially contaminated with Mycoplasma arginini . The contaminated cultures differed from mycoplasma-free cells in cell distribution for chromosome number . The frequency of cells with modal chromosome number 21 decreased, while that of cells with 20 chromosomes increased . Decontamination of cell culture with ciprofloxacin (10 mg/ml) and a subsequent cultivation of cell in the antibiotic-free medium did not restore the original cell distribution for chromosome number . In-53--131 days after infection, the increased frequency of chromosomal aberrations was registered . Eradication of Mycoplasma by ciprofloxacin and a long-term cultivation in antibiotic-free medium restored the frequency of chromosomal aberrations to the control level corresponding to mycoplasma-free cultures . In contaminated cultures no cyto- or genotoxic effect of ciprofloxacin was observed . These data, together with the previous ones, enable the authors to recommend ciprofloxacin to make cell cultures free from mycoplasmas with minimal risk to change the original properties of cell lines.

Ann Pharmacother, 1993 Dec, 27(12), 1467 - 9
Ciprofloxacin-induced toxic epidermal necrolysis; Moshfeghi M et al.; OBJECTIVE: To report a case of probable ciprofloxacin-induced toxic epidermal necrolysis (TEN) in an adult with systemic lupus erythematosus (SLE) . CASE SUMMARY: A 31-year-old woman with SLE developed a pruritic rash following her first dose of oral ciprofloxacin . She continued taking ciprofloxacin, and the rash progressively worsened, becoming painful and covering her entire body . She discontinued the ciprofloxacin six days later and presented to the hospital, where two days later, her rash began to desquamate with epidermal erosions and a positive Nikolsky's sign . Skin biopsy was positive for TEN . She then was transferred to a burn-treatment unit because of the severity of the skin involvement . The patient recovered following prolonged hospitalization and rehabilitation . CONCLUSIONS: Although TEN occurs rarely with ciprofloxacin, extensive postmarketing surveillance needs to be performed to determine other risk factors for its development and to establish the incidence of TEN and other severe cutaneous reactions caused by ciprofloxacin or the other fluoroquinolones.

J Infect Dis, 1993 Dec, 168(6), 1559 - 62
Low serum levels of oral antimycobacterial agents in patients with disseminated Mycobacterium avium complex disease; Gordon SM et al.; Twenty-seven human immunodeficiency virus-infected patients with disseminated Mycobacterium avium complex disease who were treated with oral antimycobacterial agents (clofazimine, ciprofloxacin, ethambutol, and rifampin) were studied to evaluate the usefulness of monitoring serum drug concentrations and testing in vitro susceptibility of M . avium complex (MAC) isolates . Twenty patients tolerated treatment with three or four antimycobacterial agents for at least 8 weeks; mycobacteremia was eradicated in 7 (35%) . The in vitro susceptibilities of MAC isolates to antimycobacterial agents were similar for these 7 and for the 13 who did not respond to antimycobacterial treatment . Serum drug levels were below the expected range in 6 of the 7 whose mycobacteremia was cleared and in 9 of the 13 nonresponders (P = .41) . These low serum concentrations of antimycobacterial drugs may be due to impaired drug absorption in patients with AIDS and disseminated MAC disease.

Eur J Clin Microbiol Infect Dis, 1993 Dec, 12(12), 965 - 7
Comparative activity of the new fluoroquinolone Bay y3118 against 177 penicillin susceptible and resistant pneumococci; Spangler SK et al.; The activity of a new fluoroquinolone, Bay y3118, was evaluated in comparison to three quinolones (ciprofloxacin, ofloxacin, lomefloxacin) and four broad-spectrum oral cephalosporins (cefpodoxime, cefuroxime, cefaclor, cefixime) against 49 penicillin-susceptible pneumococci, 77 pneumococci with intermediate resistance and 51 penicillin-resistant pneumococci . Quinolone activity was not affected by the penicillin susceptibility status of the organisms . Bay y3118 was very active against all strains, with an MIC90 of 0.015 microgram/ml . Other quinolones were less active, with MIC90s of 4 micrograms/ml (ciprofloxacin and ofloxacin) and 8 micrograms/ml (lomefloxacin) . Cephalosporin MICs rose parallel to those of penicillin . Cefuroxime and cefpodoxime were the most active cephalosporins, with MIC90s for strains showing susceptibility, intermediate resistance and resistance of 0.125-0.25, 2-4 and 4 micrograms/ml, respectively . Cefaclor and cefixime were less active, with corresponding MIC90s of 1-2, 8-16 and > 16 micrograms/ml, respectively.

J Antimicrob Chemother, 1993 Dec, 32(6), 797 - 808
In-vitro activities of quinolones against mycobacteria; Garcia-Rodriguez JA et al.; From the results of recently-published in-vitro studies, we have reviewed the activities of novel quinolones which are currently available, either commercially or for investigative purposes, against Mycobacterium tuberculosis, the atypical mycobacteria (principally the Mycobacterium avium complex, Mycobacterium chelonae, Mycobacterium xenopi, Mycobacterium marinum and Mycobacterium fortuitum) and Mycobacterium leprae . We have also evaluated the effects of the various methods for determining the susceptibilities of the mycobacteria on the in-vitro activities of these agents . Sparfloxacin, Win-57273, ciprofloxacin and ofloxacin were the most active agents overall . The in-vitro activities, efficacies in animal models, tissue and cell penetration and results of preliminary clinical investigations suggest that some of the newer quinolones might be effective alternatives to standard anti-tuberculous agents for the treatment of patients with infections caused by mycobacteria, particularly when there is resistance to the latter group of drugs.

Optom Vis Sci, 1993 Dec, 70(12), 1012 - 8
Continuous drug delivery through the use of disposable contact lenses; Lesher GA et al.; This in vitro study examined the ability of the available disposable soft contact lenses to absorb various ocular therapeutic agents and release them . After a 2-h or 4-h presoaking time, we measured the amount of drug released into fresh saline baths for up to 3 h . Drug levels were determined spectrophotometrically at the peak ultraviolet (UV) absorption wavelength for each drug . Ciprofloxacin hydrochloride, prednisolone sodium phosphate, and cromolyn sodium were found to be released from the disposable contacts at a rate that provided higher concentrations of drug for a longer period of time than would be expected with drops . Depending on the lens used these drugs were released continuously for a period of up to 3 h . Disposable lenses soaked in pilocarpine hydrochloride or idoxuridine released drug for 30 min or less . These data indicate that disposable contact lenses could provide an acceptable means of drug delivery for some situations and overcome drawbacks associated with the use of nondisposable hydrogel lenses.

J Chromatogr, 1993 Nov 17, 621(1), 105 - 9
Simultaneous assay of fluoroquinolones and theophylline in plasma by high-performance liquid chromatography; Davis JD et al.; A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of theophylline in plasma simultaneously with either ciprofloxacin, enoxacin or norfloxacin has been developed . It involves extraction of plasma with chloroform-isopropanol or dichloromethane-isopropanol prior to chromatography on a Spherisorb ODS2 column . The mobile phase is 15% acetonitrile in a phosphate buffer (pH 3.0) containing tetrabutylammonium hydrogen sulphate (4.4 mM) as an ion-pairing agent . Ultraviolet detection is carried out at 280 nm . Run time is less than 10 min for all three separations . The assays have been used to determine the effect of plasma concentrations of fluoroquinolone on theophylline clearance.

Ann Pharmacother, 1993 Nov, 27(11), 1325 - 8
Effect of multiple staggered doses of calcium on the bioavailability of ciprofloxacin; Lomaestro BM et al.; OBJECTIVE: To determine the effect on the relative bioavailability (Fr) of a staggered single dose of ciprofloxacin given two hours after a morning dose of calcium carbonate given three times daily over the three previous days . DESIGN: Thirteen male volunteers participated in this randomized, nonblinded, crossover investigation; 12 subjects were included in the final analysis . SETTING: Data collection and ciprofloxacin administration occurred at Albany Medical Center, a tertiary-care teaching institution . Calcium carbonate administration was on an outpatient basis . RESULTS: For 12 volunteers, the mean +/- SD Fr of ciprofloxacin staggered with calcium was 0.87 +/- 0.23 (noncompartmental model) and 0.98 +/- 0.27 (compartmental model) . Other statistically significant findings were a decrease in the time to maximum concentration of ciprofloxacin staggered with calcium in serum compared with ciprofloxacin alone (from 1.76 +/- 0.54 to 1.23 +/- 0.52 h in the noncompartmental model; p < 0.05), and a decrease in the same parameter (from 1.92 +/- 0.96 to 0.77 +/- 0.53 in the compartmental model; p < 0.005) . Maximum concentration of ciprofloxacin staggered with calcium was decreased in the noncompartmental model compared with ciprofloxacin alone (from 2.11 +/- 0.72 to 1.60 +/- 0.33, respectively; p < 0.05) . The elimination half-life and area under the concentration-time curve of ciprofloxacin were not significantly altered . CONCLUSIONS: Repeated doses of calcium carbonate, administered two hours before ciprofloxacin, did not significantly alter the Fr of this fluoroquinolone.

Antimicrob Agents Chemother, 1993 Nov, 37(11), 2333 - 6
Therapy of experimental murine brucellosis with streptomycin alone and in combination with ciprofloxacin, doxycycline, and rifampin; Lang R et al.; The in vivo efficacy of streptomycin (STR), doxycycline (DOX), rifampin (RIF), ciprofloxacin (CIP), and their combinations was evaluated for a Brucella melitensis experimental infection in a mouse model . Animals were infected with 2 x 10(4) to 4 x 10(4) CFU of B . melitensis intraperitoneally on day 0 and were randomized to receive, starting on day 7, STR alone at 75, 150, or 300 mg/kg of body weight per day intraperitoneally or DOX at 6 mg/kg/day orally, RIF at 3 mg/kg/day orally, or CIP at 200 mg/kg/day orally, each of the last three drugs alone or in combination with STR at 75, 150, or 300 mg/kg/day, for 14 days . Therapy failure (defined as nonsterile spleens) was observed in all animals treated with STR at all doses and with CIP given as monotherapy . Mean log CFU isolated from the spleens remaining infected following monotherapy with STR or CIP were not different from those in control mice . RIF at a low dose did not have an effect on cure rates; however, a reduction in CFU relative to the CFU in untreated animals was obtained . DOX at low levels achieved a 35% cure rate and a reduction in CFU in animals not cured . All animals treated with DOX or RIF combined with any STR dose were cured, but none of the animals receiving the STR-CIP combinations was cured, and the splenic CFU remained similar to those in the controls . These results demonstrate that the combinations DOX-STR and RIF-STR are synergistic against B . melitensis, while the combination STR-CIP is indifferent and ineffective in the management of acute murine brucellosis . The results also appear to support the clinical superiority of combination drug therapy over monotherapy.

Kekkaku, 1993 Nov, 68(11), 723 - 30
{Expectation of new antituberculous drugs and targeting therapy for treatment of mycobacterial infections}; Tomioka H; Recent AIDS endemic causes the worldwide increase in intractable mycobacterial infections including extrapulmonary tuberculosis due to drug resistant organisms and disseminated Mycobacterium avium complex infections . Therefore, new antituberculous (antimycobacterial) drugs and development of regimens and protocols for clinical treatment of such mycobacterial infections are urgently needed . Here, I described the present situations of new antituberculous agents, in particular new rifamycin derivatives including rifabutin and benzoxazinorifamycin (KRM-1648), new macrolides such as clarithromycin and azithromycin, and new quinolones including sparfloxacin, ofloxacin, ciprofloxacin, fleroxacin, AM-1155 and so on . Their in vitro antimycobacterial activities, therapeutic efficacy against experimental infections induced in animals especially in mice, and clinical trials using these drugs are summarized by referring to recent studies by worldwide investigators including us . Moreover, this paper dealt with some of recent attempts for chemotherapy of mycobacterial infections employing the drug delivery system using liposomal microvesicles as a carrier of drugs . Although these new drugs and development in new regimens appreciably potentiated the efficacy of controlling mycobacterial infections, in particular M . avium complex infections, it remains very difficult to achieve a complete elimination of the organisms from the sites of infection, even if provided multi-drug regimens using new drugs having excellent antimycobacterial activity and sufficient dosages . Therefore, it seems important to make an effort to elucidate the mechanisms of induction of immuno-unresponsiveness in hosts in progressed state of mycobacterial infection, as well as to develop new drugs possessing more potent antimycobacterial activity.

Med Clin North Am, 1993 Nov, 77(6), 1253 - 62
Pharmacology of the antimycobacterial drugs; Peloquin CA; The management of MDR-TB requires that the clinician become familiar with the "second-line" antimycobacterial agents . These drugs are generally less potent and frequently more toxic than isoniazid and rifampin . Because they are less active, innovative dosing schedules may allow us to take advantage of the few strengths that they possess . This approach will require further research into the dose-response relationships for each agent . Based on our current knowledge of these drugs, practical guidelines for their use have been described . These guidelines include the gradual escalation of the oral doses of PAS, cycloserine, and ethionamide over several days, and the intravenous administration of streptomycin and capreomycin . Both ciprofloxacin and ofloxacin may be used for the treatment of MDR-TB, but data from clinical trials are currently lacking . Finally, because patients with AIDS appear to develop antimycobacterial drug malabsorption over the course of their HIV infection, therapeutic drug monitoring can be used to verify drug absorption in the individual patient . This approach may improve therapy for that patient and prevent the selection of additional drug resistance.

J Infect Dis, 1993 Nov, 168(5), 1289 - 92
Efficacy of azithromycin for treating Babesia microti infection in the hamster model; Weiss LM et al.; Because of its prevalence and severity, Babesia microti infection is an important public health problem . The current treatment of choice is clindamycin plus quinine . However, in some cases other treatments are needed because of drug intolerance or relapse . The activity of azithromycin was investigated for treatment of babesiosis in the hamster model . All animals received vancomycin to prevent antibiotic-associated colitis . Quinine (250 mg/kg/day), azithromycin (150 mg/kg/day), and the combination of azithromycin and quinine were compared . A significant suppression of parasitemia was found in all treatment groups (combination had the greatest effect, followed by azithromycin, then quinine; P < .05) . The mean survival was significantly prolonged in the combination group (P < .05) . Azithromycin as monotherapy in a higher dose (300 mg/kg/day) also resulted in a significant prolongation of survival (P < .05) . Spirogermanium and ciprofloxacin, which have been reported to have antimalarial activity, had no effect on parasitemia or survival in this experimental babesiosis model.

Gen Pharmacol, 1993 Nov, 24(6), 1393 - 401
Only some anticonvulsants protect against seizures induced by aminophylline in quinolone-treated genetically epilepsy prone rats; De Sarro A et al.; 1 . The effects of some anticonvulsant drugs against seizures induced by a combined treatment with aminophylline and quinolone in genetically epilepsy-prone rat have been investigated . 2 . Animals were intraperitoneally pretreated with carbamazepine, diazepam, phenobarbital, CPPene and dizocilpine or saline and 15 min later administered orally with 51.86 mumol/kg b . wt of either cinoxacin or ciprofloxacin . 60 min after quinolones, rats received intraperitoneally aminophylline (100, 120, 140, 160 or 180 mg/kg b . wt) . 3 . Ciprofloxacin showed to be more effective than cinoxacin in potentiating the aminophylline convulsant effects . 4 . Neither carbamazepine nor diazepam and phenobarbital, at the lowest dose used, elicited any effect in reducing the aminophylline-induced seizures in both cinoxacin- and ciprofloxacin-treated animals . Whereas, diazepam and phenobarbital when administered i.p . at 2.5 and 60 mg/kg b . wt respectively demonstrated protective properties . 5 . CPPene and dizocilpine, two excitatory amino acid antagonists, were both very effective in antagonizing the seizures produced by concomitant treatment with cinoxacin or ciprofloxacin plus aminophylline . 6 . The present results suggest an involvement of the excitatory amino acid receptors in mediating the seizures induced by the combined treatment with quinolones and aminophylline.

J Pharm Technol, 1993 Nov-Dec, 9(6), 246 - 8
Cost of inappropriate use of ciprofloxacin in ambulatory care; Koo JM et al.; OBJECTIVE: To determine the incidence of inappropriate ciprofloxacin use and the resulting cost thereof in ambulatory care . DESIGN: Retrospective cost analysis . SETTING: Ambulatory care clinic of a Department of Veterans Affairs Medical Center . PATIENTS: One hundred thirty-seven ambulatory patients prescribed ciprofloxacin during March, April, and May 1992 . Forty-six patient charts were available for review . MAIN OUTCOME MEASURE: Indications for ciprofloxacin use were determined from chart review . RESULTS: Chart review of 46 of the 137 patients prescribed ciprofloxacin during the three-month study period indicated that only 8 (17 percent) had infections that were appropriately treated with this antibiotic . If 550 patients had received ciprofloxacin that year (figure extrapolated from the three-month totals), the cost of prescribing would have been $29,260 . This study indicates that $20,500 per year could be saved by prescribing equally efficacious oral antibiotics . CONCLUSIONS: Restricting ciprofloxacin use to its proven indications in the ambulatory setting may result in considerable cost savings to medical centers.

Laryngoscope, 1993 Oct, 103(10), 1081 - 3
Increased cytotoxicity of squamous cell carcinoma of the head and neck by combining cisplatin with VP-16 and ciprofloxacin; Haller J et al.; Chemotherapeutic treatment of squamous cell carcinoma (SCC) of the head and neck has been largely ineffective because of tumor cell resistance . This study examined combinations of cisplatin, 4' demethylepipodophyllotoxin ethylidene D-glucoside (VP-16), and ciprofloxacin, a quinolone antibiotic . VP-16 and ciprofloxacin were used in an effort to inhibit DNA repair and increase cytotoxicity . Chemotherapeutic agents often have a direct damaging effect on cellular DNA . Cytotoxicity may be the result of incomplete DNA repair mechanisms; whereas tumor cell resistance to drugs may be due to efficient DNA recovery . A nuclear enzyme especially important to DNA repair and cell growth is topoisomerase II (topo II) . Targeted inhibition of topo II by VP-16 and ciprofloxacin may cause increased cisplatin cytotoxicity . SCC cell lines of head and neck origin were treated with a combination of cisplatin, VP-16, and/or ciprofloxacin with cell viability being assessed by the MTT colorimetric assay . Four of five SCC lines examined demonstrated significant augmentation of cisplatin cytotoxicity with the addition of both VP-16 and ciprofloxacin . These in vitro data suggest methods may exist for improving the chemotherapeutic treatment of SCC of the head and neck.

Clin Pharmacol Ther, 1993 Oct, 54(4), 368 - 73
Intravenous ciprofloxacin disposition in obesity; Allard S et al.; The pharmacokinetics of ciprofloxacin and its metabolite 1 (desethyleneciprofloxacin) were studied in 17 obese men (mean age, 29.2 +/- 7.5 years; mean weight, 110.7 +/- 20.2 kg; mean body mass index, 36.4 +/- 3.9 kg/m2) and 11 control subjects (men of normal weight; mean age, 25.0 +/- 5.1 years; mean weight, 71.8 +/- 9.9 kg; mean body mass index, 23.3 +/- 2.4 kg/m2) . Each subject received a single 400 mg intravenous dose of ciprofloxacin infused over 1 hour . Ciprofloxacin total clearance was significantly increased in obese subjects compared with control subjects (897.44 +/- 159.57 versus 744.44 +/- 120.51 ml/min, respectively; p < 0.05) . Ciprofloxacin renal clearance in obese subjects (637.58 +/- 128.89 ml/min) was 29% higher than in control subjects (495.47 +/- 137.85 ml/min; p < 0.05) . The elimination half-life values of ciprofloxacin and desethyleneciprofloxacin were not statistically different between groups . Ciprofloxacin steady-state volume of distribution (Vss) was significantly larger in obese group (269.17 +/- 51.64 versus 219.03 +/- 35.80 L; p < 0.01) compared with the control group, and when it was normalized by total body weight, obese subjects exhibited lower Vss/kg than control subjects (2.46 +/- 0.42 versus 3.06 +/- 0.31 L/kg; p < 0.001) . These findings indicate that ciprofloxacin is distributed less to adipose tissue than to other tissues, but partial distribution to adipose tissue does occur . To normalize the volume of distribution of obese subjects to that of normal weight subjects, 45% of excess weight (total body weight minus ideal body weight) must be added to the ideal body weights of obese subjects.

Am J Kidney Dis, 1993 Oct, 22(4), 598 - 602
Ciprofloxacin-induced granulomatous interstitial nephritis and localized elastolysis; Lien YH et al.; Ciprofloxacin is known to cause acute interstitial nephritis . We report the first case of ciprofloxacin-induced granulomatous interstitial nephritis and localized elastolysis . The patient presented with acute renal failure and skin lesions following a 14-day course of ciprofloxacin administered for cellulitis . The patient had symmetric, palm-sized, tender violaceous plaques on both axillae . The renal biopsy revealed granulomatous interstitial disease . A skin biopsy revealed an elastolytic process with histocytic infiltration and calcification . After discontinuing ciprofloxacin and starting a short course of steroid therapy, the skin lesion and renal function improved promptly . The nephritis relapsed after prednisone was discontinued and responded to a second course of steroid therapy . Ciprofloxacin, like penicillin, can cause granulomatous interstitial nephritis and elastolysis . A prolonged course of steroid therapy may be indicated in patients with ciprofloxacin-induced granulomatous interstitial nephritis to avoid early relapse.

Surgery, 1993 Oct, 114(4), 828 - 34; discussion 834-5
The pull-through procedure: technical factors in influencing outcome, with emphasis on pouchitis; Fischer JE et al.; BACKGROUND . The purpose of the study was to review those features that we believed to be critical to the successful performance of the ileal pouch-anal anastomosis, or pull-through, procedure, and specifically the complication of pouchitis . METHODS . The charts of 205 patients who successfully underwent ileal pouch-anal anastomosis procedure were reviewed . No follow-up was available in five patients; therefore, the basis of this report and its analysis was based on 200 consecutive procedures in which at least two of the three surgeons participated . Particular emphasis was placed on continence, particularly nighttime continence . The incidence of pouchitis, either a single episode or intermittent episodes, was surveyed . Particular attention was paid to the level of rectal mucosectomy and anastomosis at the top of the columns of Morgagni, thus retaining the transitional zone . RESULTS . Only 5% of patients were incontinent in the absence of pouchitis . Twenty-five patients (13%) wore a pad at night, but only nine (5%) wore a pad during the day . Of those patients with pouchitis, 6% (12) have had a single episode and 12% (23) were intermittently on medication . Therapy of pouchitis was usually carried out with ciprofloxacin 500 mg by mouth everyday or twice a day . CONCLUSIONS . Ileal pouch-anal anastomosis is an excellent procedure, provided technical details are adhered to . Satisfactory outcome with respect to nighttime continence can be achieved with rectal mucosectomy with minimal manipulation and retaining the transitional epithelium, performing the pouch anastomosis at the top of the columns of Morgagni . The incidence of pouchitis is disappointing but need not be inhibiting of either patients or carrying out this life-saving procedure in patients with ulcerative colitis and familial polyposis.

Br J Clin Pharmacol, 1993 Sep, 36(3), 195 - 200
Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in male nonsmokers; Loi CM et al.; 1 . The individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism were examined in six young male nonsmokers . 2 . Treatment sequence consisted of 7 days each of cimetidine 400 mg p.o . every 12 h . ciprofloxacin 500 mg p.o . every 12 h, and the combination of cimetidine and ciprofloxacin . 3 . Studies of theophylline pharmacokinetics were performed at baseline and on the fifth day of each regimen . 4 . Individually, cimetidine and ciprofloxacin decreased the clearance of theophylline by 25% and 32%, respectively . Therapy with the combined regimen resulted in a 41% reduction in theophylline clearance, which was greater than that achieved with each drug alone (P < 0.01) . 5 . Ciprofloxacin, in contrast to cimetidine, inhibited N-demethylations of theophylline to a significantly greater extent than the hydroxylation pathway . Combined treatment produced a further decline in formation of 1,3-dimethyluric acid than each drug alone . 6 . These data suggest that coadministration of cimetidine and ciprofloxacin exerts a greater impairment of theophylline biotransformation than each inhibitor alone . The enhanced inhibitory effect from the two inhibitors will occur only when sub-maximal doses of each individual agent are used.

Pharmacotherapy, 1993 Sep-Oct, 13(5), 461 - 4
A follow-up safety study of ciprofloxacin users; Jick SS et al.; We followed 37,233 outpatients for 45 days after receiving a prescription for ciprofloxacin to identify any newly diagnosed, important illnesses that might have been caused by the drug . For 29 users the role of ciprofloxacin in the etiology of the illness could not be confidently ruled out (7.79/10,000 persons; 95% CI 5.42-11.18) . In only seven was a causal relation to ciprofloxacin considered likely: three skin reactions and one case each of thrombocytopenia, "headache, nausea, and shakes," hallucinations, and palpitations . No fatal illnesses occurred, and all patients recovered after discontinuing the drug . In addition, few cases of photosensitivity were associated with the agent . We conclude that important adverse reactions attributable to ciprofloxacin are uncommon.

Antimicrob Agents Chemother, 1993 Sep, 37(9), 1799 - 806
Anti-Mycobacterium avium activity of quinolones: in vitro activities; Klopman G et al.; The MICs of 88 quinolones against 14 selected reference and clinical strains of Mycobacterium avium-M . intracellular complex were determined . Agents tested included ciprofloxacin, sparfloxacin (PD 131501), and 86 other experimental quinolones . Test strains were selected to represent various susceptibilities to ciprofloxacin and other drug resistance profiles . MICs were determined by the microdilution method in 7HSF broth, with incubation for 14 days at 35 degrees C . The results showed 25 of the quinolones to be active against the strains, with MICs for 90% of the strains (MIC90s) of 2 to 32 micrograms/ml . Ten of these compounds had activities equivalent to or greater than that of ciprofloxacin . The most active compound was PD 125354, with an MIC50 of 0.5 micrograms/ml and an MIC90 of 2 micrograms/ml; comparable values for ciprofloxacin were 4 and 8 micrograms/ml, respectively . The next most active compounds, with MIC90s of 4 micrograms/ml, were sparfloxacin (PD 131501), PD 123982, PD 135144, and PD 119421 . MIC90s of PD 131575, PD 126889, PD 122642, PD 139586, and PD 143289 were 8 micrograms/ml . Further evaluation of the most active agents is warranted, as is assessment of structure-activity relationships of active and inactive agents to elucidate the active portions of the compounds and to lead to the development of compounds with enhanced activity.

J Infect, 1993 Sep, 27(2), 177 - 80
Treatment of recalcitrant actinomycosis with ciprofloxacin; Macfarlane DJ et al.; We describe a case of actinomycosis with several unusual features . The patient has been under medical supervision for more than 20 years; the disease has spread in an atypical manner and did not respond to standard therapy . Finally, there has been an unexpected response to a prolonged course of a member of the quinolone group of antibiotics.

Arch Int Pharmacodyn Ther, 1993 Sep-Oct, 325, 86 - 95
Alpha 1-adrenoceptor-blocking activity of ofloxacin and ciprofloxacin in isolated vascular smooth muscles; Ito K et al.; Using vascular strips from dogs and rabbits, we investigated whether the hypotensive action of ofloxacin enantiomers could be ascribed to effects on vascular smooth muscle . (+)-Ofloxacin, (-)-ofloxacin, (+/-)-ofloxacin and ciprofloxacin competitively inhibited contractions induced by norepinephrine or phenylephrine in dog mesenteric artery and rabbit aortic smooth muscles, without affecting the maximum contractions, whereas they did not affect contractions induced by high KCl . (-)-Ofloxacin did not affect the contractions induced by prostaglandin F2 alpha, 5-hydroxy-tryptamine, U46619 and angiotensin II . Pretreatment with (-)-ofloxacin protected alpha 1-receptors of rabbit aortas from the irreversible blockade by phenoxybenzamine . Any action on the vascular endothelium or intracellular Ca release was not involved in the vasorelaxing action of the drugs . The results suggest that these drugs have an antagonistic action on alpha 1-adrenoceptors in vascular smooth muscles and that this action is, at least partly, responsible for the hypotensive action.

Antimicrob Agents Chemother, 1993 Sep, 37(9), 1764 - 70
Involvement of inhibitory and excitatory neurotransmitters in levofloxacin- and ciprofloxacin-induced convulsions in mice; Akahane K et al.; We studied the effects of gamma-aminobutyric acid (GABA)-benzodiazepine receptor agonists and glutamate receptor antagonists on levofloxacin (LVFX)- and ciprofloxacin (CPFX)-induced convulsions using intrathecal (i.t.) injections in mice . We also studied the effects of these agonists and antagonists on exacerbated convulsions induced by coadministration of the quinolone with 4-biphenylacetic acid (BPAA) . The agonists or antagonists were injected i.t . 5 min and BPAA was administered orally 30 min before a single i.t . injection of the quinolone (10 microliters per animal) . The animals were observed for clonic convulsion and death, and latency times to the appearance of convulsion were determined . Among the agonists, baclofen showed marked inhibition of both LVFX- and CPFX-induced convulsions, while other compounds such as GABA, muscimol, diazepam, and 3-aminopropylphosphonic acid had slight effects . Among the antagonists, kynurenic acid showed the strongest inhibition of convulsions caused by all doses of LVFX and CPFX and prolonged latency times; gamma-glutamyl-aminomethylsulfonic acid (GAMS) also markedly inhibited convulsions . The antagonists D-AP-5, AP-7, and 6,7-dinitroquinoxaline-2,3-dione (DNQX) had slight effects . Additionally, GAMS, DNQX, and MK-801 significantly lowered the incidence of death in the groups treated with CPFX . The enhanced convulsive activities of LVFX or CPFX by pretreatment with BPAA were clearly blocked by baclofen, kynurenic acid, GAMS, and DNQX . D-AP-5 and AP-7 also showed clear effects on the activity of LVFX . These results suggest that LVFX has fewer effects on the brains than CPFX and that convulsions induced by these quinolones alone and by these quinolones administered with BPAA may be mediated largely through glutamate and GABA(B) rather than GABA(A) receptors in mice.

J Chromatogr, 1993 Aug 11, 617(2), 329 - 33
Determination of ciprofloxacin levels in chinchilla middle ear effusion and plasma by high-performance liquid chromatography with fluorescence detection; Lovdahl M et al.; An isocratic high-performance liquid chromatographic method has been developed to determine ciprofloxacin levels in chinchilla plasma and middle ear fluid . Ciprofloxacin and the internal standard, difloxacin, were separated on a Keystone ODS column (100 x 2.1 mm I.D., 5 microns Hypersil) using a mobile phase of 30 mM phosphate buffer (pH 3), 20 mM triethylamine, 20 mM sodium dodecyl sulphate-acetonitrile (60:40, v/v) . The retention times were 3.0 min for ciprofloxacin and 5.2 min for difloxacin . This fast, efficient protein precipitation procedure together with fluorescence detection allows a quantification limit of 25 ng/ml with a 50 microliters sample size . The detection limit is 5 ng/ml with a signal-to-noise ratio of 5:1 . Recoveries (mean +/- S.D., n = 5) at 100 ng/ml in plasma and middle ear fluid were 89.4 +/- 1.2% and 91.4 +/- 1.6%, respectively . The method was evaluated with biological samples taken from chinchillas with middle ear infections after administering ciprofloxacin.

Antimicrob Agents Chemother, 1993 Jul, 37(7), 1497 - 503
Quinolones potentiate cefazolin-induced seizures in DBA/2 mice; De Sarro A et al.; The behavioral and convulsant effects of cefazolin, a beta-lactam derivative, were studied after intraperitoneal administration to DBA/2 mice, a strain genetically susceptible to sound-induced seizures, and Swiss mice . DBA/2 mice were more susceptible to seizures induced by cefazolin than were Swiss mice . The proconvulsant effects of some quinolones on seizures evoked by intraperitoneal administration of cefazolin were also evaluated in DBA/2 mice . Our study also demonstrated that the order of proconvulsant activity in our epileptic model was pefloxacin > enoxacin > ofloxacin > rufloxacin > norfloxacin > cinoxacin > ciprofloxacin > nalidixic acid . The relationships between the chemical structures and proconvulsant activities of quinolone derivatives were studied . The relationship between lipophilicity and proconvulsant activity was also investigated.

Toxicol Lett, 1993 Jul, 69(1), 1 - 14
Effects of ciprofloxacin and enrofloxacin on zoxazolamine kinetics, plasma concentration and sleeping times in mice; Vancutsem PM et al.; The treatment of CD1 male mice with either ciprofloxacin (CP) or enrofloxacin (EF) prior to zoxazolamine (ZX) administration increased the mean ZX sleeping times to, respectively, 162 and 156% of the control (ZX alone) . At the end of the sleeping time, the mean ZX plasma concentration in controls was 27.2 micrograms/ml and was not different in EF- or CP-treated groups (87% and 95% of controls, respectively) . The animals coadministered with CP or EF and ZX eliminated the latter more slowly than the controls . The estimated zero-time drug concentration of the disposition curves of both the CP- and EF-treated groups as well as the apparent half-life of elimination and apparent overall rate of elimination of the CP-treated group were different from the control values.

CLAO J, 1993 Jul, 19(3), 166 - 8
Deposition of ciprofloxacin, prednisolone phosphate, and prednisolone acetate in SeeQuence disposable contact lenses; Macsai MS et al.; We noted opaque deposits in SeeQuence disposable contact lenses in three patients with persistent epithelial defects who were being treated with topical ciprofloxacin and prednisolone acetate . In each patient, the contact lenses with deposits were removed and replaced . High performance liquid chromatography analysis revealed the deposits to be precipitates of ciprofloxacin and prednisolone acetate . We incubated new SeeQuence disposable contact lenses in ciprofloxacin, prednisolone phosphate, and prednisolone acetate alone and in combination . Precipitates did form when ciprofloxacin was combined with either prednisolone acetate or prednisolone phosphate . We recommend removal and replacement of contact lenses should these deposits develop to prevent the possibility of corneal toxicity.

Ann Pharmacother, 1993 Jul-Aug, 27(7-8), 928 - 37
Controversies in the management of Mycobacterium avium complex infection in AIDS patients; Peloquin CA; OBJECTIVE: To update readers on the clinical management of infections secondary to Mycobacterium avium complex (MAC) in patients with AIDS . A general description of the organism, culture and susceptibility testing, and clinical manifestations of the disease is provided . Several aspects of the treatment of the disease, including an historical perspective, current approaches, and future research opportunities, are described . DATA SOURCES: Current medical literature, including abstracts presented at international meetings, is reviewed . References were identified through MEDLINE, Current Contents, and published meeting abstracts . STUDY SELECTION: Data regarding the epidemiology, clinical manifestations, culture and susceptibility testing, and treatment of MAC are cited . Specific attention is given to the management of patients with MAC infection . DATA EXTRACTION: Information contributing to the discussion of the topics selected by the author is reviewed . Data supporting and disputing specific conclusions are presented . DATA SYNTHESIS: Disseminated MAC infection is diagnosed antemortem in approximately 30 percent of patients with AIDS; postmortem rates of isolation exceed 50 percent . The incidence of MAC may increase as attempts at isolating the organism become more aggressive . The traditional approach to the isolation, susceptibility testing, and treatment of MAC has been derived from the management of Mycobacterium tuberculosis, with disappointing results . Newer radiometric in vitro methods of susceptibility testing appear to show more promise . Current mouse models of MAC are not true AIDS models; new CD4-deficient mouse models are being developed . Clinical mycobacteriologic and pharmacokinetic laboratory support have been underused, with treatment generally proceeding empirically . New agents that may contribute to the management of disseminated MAC infection include the macrolide derivatives clarithromycin and azithromycin . Research also continues with new rifamycins (including rifabutin) and fluoroquinolones (ciprofloxacin, sparfloxacin) . Preliminary results suggest a central role for macrolides in the treatment of disseminated MAC; effective companion drugs are needed to prevent the rapid emergence of macrolide-resistant MAC . CONCLUSIONS: Treatment results for disseminated MAC infection remain poor . Therapy may be improved by selecting drugs on the basis of susceptibility data for each isolate, rather than by using empiric regimens based on susceptibility trends . Significant antimycobacterial drug malabsorption has been documented, and may contribute to poor outcomes . More-potent agents are needed to improve the clinical outcome in AIDS patients with MAC.

Indian J Physiol Pharmacol, 1993 Jul, 37(3), 232 - 4
Unwanted effects of ciprofloxacin in Indian population; Grover JK; The present study was an attempt to evaluate epidemiological profile of adverse reactions of ciprofloxacin and factors influencing them in Indian population . The study was conducted in indoor patients of All-India Institute of Medical Sciences, New Delhi . The patients were in the age group of 21-65 years . Gastrointestinal upsets (nausea, vomiting, abdominal discomfort), headache, dizziness and skin rash were observed . Route of administration influenced the onset of ADRs . Severity of ADRs was proportional to dose . All reactions were reversible and the incidence of ADRs is lower in Indian population as compared to USA(1) but higher than seen in Japanese (2).

Exp Gerontol, 1993 Jul-Oct, 28(4-5), 421 - 33
Aging and the response to inhibition and induction of theophylline metabolism; Vestal RE et al.; The twofold to threefold higher incidence of adverse drug reactions in elderly as opposed to younger patients is due mainly to more severe disease and the requirement for more complex drug treatment regimens . The incidence of adverse drug reactions increases with the number of prescribed drugs . Because of multiple drug use by the elderly, the potential for drug interactions is greater in this patient group . Surprisingly, the effect of age on the clinical pharmacology of drug interactions has not been thoroughly investigated . Our studies have shown that cimetidine inhibits and phenytoin induces the metabolism of theophylline to a similar extent in healthy male nonsmokers and smokers . Preliminary analysis of the results of a study to investigate the inhibition of theophylline metabolism by cimetidine and ciprofloxacin administered in combination to healthy male and female nonsmokers also does not show an age difference in response . Additional careful studies are needed to evaluate further the pharmacology and clinical importance of pharmacokinetic and pharmacodynamic drug interactions in the elderly.

Arch Ophthalmol, 1993 Jun, 111(6), 827 - 30
Treatment of chronic postfiltration hypotony by intrableb injection of autologous blood; Wise JB; OBJECTIVE--To treat chronic hypotony with decreased vision after filtration surgery . DESIGN--After observation from 3 1/2 to 13 months with no spontaneous improvement, eyes were treated with the experimental therapy and followed up closely to determine the results . PATIENTS--Four eyes with chronic hypotony, selected from a series of 125 eyes receiving trabeculectomy augmented by intraoperative mitomycin . All eyes had posterior chamber pseudophakia . All eyes had postoperative laser cutting of sutures holding the scleral flap of the trabeculectomy . INTERVENTION--After administration of topical prophylactic 0.3% ciprofloxacin hydrochloride and topical anesthetic, the bleb was inflated with whole autologous blood through a 27-gauge needle passed subconjunctivally into the bleb . MAIN OUTCOME MEASURES--Change in intraocular pressure, change in vision, change in choroidal detachment, any type of complication . RESULTS--Average intraocular pressure increased from 5.5 to 8.2 mm Hg . Average vision improved from 20/148 to 20/33 . In two eyes with choroidal detachment, the detachment absorbed in one eye and decreased in the other . No complications occurred . CONCLUSION--Intrableb injection of autologous blood deserves further study as a possible treatment for hypotony following filtration.

Cancer, 1993 Jun 1, 71(11), 3640 - 6
Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer; Rubenstein EB et al.; BACKGROUND . Hospitalization and intravenous (IV) broad-spectrum antibiotics are the standard of care for all febrile neutropenic patients with cancer . Recent work suggests that a low-risk population exists who might benefit from an alternate approach . METHODS . A prospective randomized clinical trial was performed comparing oral ciprofloxacin 750 mg plus clindamycin 600 mg every 8 hours with IV aztreonam 2 g plus clindamycin 600 mg every 8 hours for the empiric outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer . RESULTS . The oral regimen cured 35 of 40 episodes (88% response rate), whereas the IV regimen cured 41 of 43 episodes (95% response rate, P = 0.19) . Although the cost of the oral regimen was significantly less than that of the IV regimen (P < 0.0001), it was associated with significant renal toxicity (P < 0.05), which led to early termination of the study . Overall, combining its safety and efficacy, the IV regimen was superior (P = 0.03) . CONCLUSIONS . This prospective study suggested that outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer is safe and effective . Better oral regimens are needed.

Ann Pharmacother, 1993 Jun, 27(6), 704 - 7
Physical and chemical compatibility of intravenous ciprofloxacin with other drugs; Jim LK; OBJECTIVE: To determine the physical and chemical compatibilities of ciprofloxacin lactate infusion with other commonly used intravenously administered drugs . DESIGN: Ciprofloxacin lactate injection in a commercially available concentration of 2 mg/mL was mixed with 15 intravenous drugs during simulated Y-site injection . Ciprofloxacin was mixed with usually employed concentrations of other drugs in a 1:1 ratio and examined physically by visual inspection and chemically by HPLC analysis . Adsorption of ciprofloxacin to intravenous administration sets with or without inline filters was also studied . SETTING: The study was carried out at ambient temperature (25 degrees C) under fluorescent lighting except for vitamin B complex, which was protected from light . All samples were prepared in a laminar airflow hood . MAIN OUTCOME MEASURES: Physical incompatibility was determined by visual inspection against a black-and-white background, and chemical incompatibility was measured by a stability-indicating HPLC assay for ciprofloxacin . Concentrations determined at time zero (before mixing) were defined as 100 percent . Values estimated for each sample at subsequent time points were calculated as percentages of the initial concentration . Recovery below 90 percent of the initial concentration is defined as significant loss . RESULTS: Of the 15 drugs studied, only heparin, furosemide, and teicoplanin were found to be incompatible with ciprofloxacin . Adsorption of ciprofloxacin to administration sets with and without inline filters was minimal . Metronidazole was also found to decrease to 90 percent of its initial concentration immediately upon mixing . CONCLUSIONS: Ciprofloxacin ready-to-infuse solution is compatible with most of the drugs studied except heparin, furosemide, teicoplanin, and, perhaps, metronidazole . Because only the stability and potency of ciprofloxacin were studied, further testing is needed to confirm if any chemical deterioration of the other drugs occurred when combined with ciprofloxacin.

Int J Dermatol, 1993 Jun, 32(6), 413 - 6
Photosensitizing potential of ofloxacin; Scheife RT et al.; BACKGROUND . The relative phototoxic risk of ofloxacin, one of the newer fluoroquinolones, was compared with that of an active control of known but low phototoxic risk, naproxen . METHODS . A randomized, controlled, open-label trial was used with a standardized phototoxic assay completed at baseline, midway through, and at the termination of the 12-day trial . The trial was held at a dermatology research laboratory located at a large tertiary referral and teaching hospital . Thirty healthy volunteers who met the inclusion criteria and met none of the exclusion criteria were enrolled . Twenty-seven patients completed the trial . Three subjects failed to complete the trail . One subject developed an exaggerated response to the initial photoexposure and was dropped from the study . The other two subjects failed to return for follow-up visits . RESULTS . Both ofloxacin and the active control agent, naproxen, significantly increased the subjects' response to the tested solar and ultraviolet irradiation . There was, however, no significant difference between the responses observed for ofloxacin versus naproxen at any time . CONCLUSIONS . Ofloxacin possesses a definite but low potential to cause phototoxic reactions in humans . These study data, in concert with surveillance data, suggest a hierarchy of phototoxic risk among the fluoroquinolones: fleroxacin >> lomefloxacin, pefloxacin >> ciprofloxacin > enoxacin, norfloxacin, ofloxacin . The impact that phototoxicity risk will have on selecting the optimum member of a large drug family appears to be substantial in outpatient and ambulatory settings and minimal in inpatient settings.

Arch Intern Med, 1993 May 24, 153(10), 1258 - 62
Ciprofloxacin-induced nephrotoxicity in patients with cancer; Lo WK et al.; Nephrotoxicity associated with ciprofloxacin is uncommon . Five patients with cancer who developed acute renal failure that followed treatment with ciprofloxacin are described and an additional 15 cases reported in the literature are reviewed . Other than elevation of serum creatinine levels, characteristic clinical manifestations and abnormal laboratory findings are not frequently present . Allergic interstitial nephritis is believed to be the underlying pathological-process . Definitive diagnosis requires performance of renal biopsy, although this is not always feasible . An improvement in renal function that followed the discontinuation of the offending antibiotic supports the presumptive diagnosis of ciprofloxacin-induced acute renal failure.

Antimicrob Agents Chemother, 1993 May, 37(5), 1065 - 72
Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin; Forrest A et al.; Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin . Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h . Plasma samples (2 to 19 per patient; mean +/- standard deviation = 7 +/- 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin . These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient . The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator . Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 {OSS2} was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values . These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient . Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CLT in liters per hour) was related to body size and renal function (creatinine clearance {CLCR} in milliliters per minute per 1.73 m2) by the equation CLT = (0.00145.CLCR + 0.167).weight . However, only 30% of the variance in CLT was explained by this relationship, and no other patient covariates were significant . Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CLT (by 44%; P < 0.001) than weight- and CLCR- matched stable volunteers . OSSs provided parameter estimates that showed good to excellent estimates of CLT (or area under the concentrations-time curve {AUC}) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was > 0.99) and concentration-time profiles were accurately reconstructed . These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.

Ann Pharmacother, 1993 May, 27(5), 586 - 8
Effect of seven fluoroquinolones on the determination of serum creatinine by the picric acid and enzymatic methods; Massoomi F et al.; OBJECTIVE: To investigate in vitro the interaction of seven fluoroquinolone antibiotics with the determination of serum creatinine by the picric acid and enzymatic methods . DESIGN: This blind, in vitro study assayed duplicate serum samples for creatinine by the picric acid and enzymatic methods with averaged spiked concentrations of 2.71, 13.56, 27.12, and 108.47 mumol/L of ciprofloxacin, fleroxacin, lomefloxacin, ofloxacin, 1-ofloxacin, sparfloxacin, and temafloxacin . Cefoxitin (in concentrations of 233.9, 1169.6, 1754.4, and 2339.2 mumol/L) was used as a positive control for the picric acid assay . SETTING: University-affiliated hospital, Department of Pharmaceutical Services and Clinical Chemistry section of the Department of Pathology . MAIN OUTCOME MEASURE: The serum creatinine samples spiked with the seven substituted fluoroquinolones and cefoxitin were assayed by both the picric acid and enzymatic assays . Statistical analysis compared the spiked samples with blank serum by Student's t-test and concentration ranges were compared by analysis of variance . A statistically significant interference with serum creatinine was p < 0.05 . RESULTS: None of the substituted fluoroquinolones interfered significantly with the determination of serum creatinine by either method . Cefoxitin significantly interfered with the determination of serum creatinine by the picric acid method . CONCLUSIONS: Fluoroquinolones do not interfere with the determination of serum creatinine by either the picric acid or enzymatic method.

Allergy, 1993 May, 48(4), 296 - 7
Fixed eruption caused by ciprofloxacin with cross-sensitivity to norfloxacin; Alonso MD et al.; A case of fixed eruption caused by ciprofloxacin is reported . To our knowledge, no other cases have been published . Cross-sensitivity with another fluoroquinolone has been demonstrated.

Rev Hosp Clin Fac Med Sao Paulo, 1993 May-Jun, 48(3), 116 - 8
{Effect of quinolones on mice experimental infection by Plasmodium berghei and their possible therapeutic usefulness}; Amato Neto V et al.; The search for new antimalarial drugs is important for many reasons, specially because of the resistance of plasmodia . Some clinical and laboratory studies have recently indicated that quinolones, currently in use for treatment of bacterial infections, have antimalarial activity . So, we evaluated the possible action of ciprofloxacin, norfloxacin, ofloxacin and pefloxacin in mice experimentally infected by Plasmodium berghei, by the oral route . Taking into account parasitemia and mortality, we came to conclusion that these drugs are not effective, as judged by the methods used.

Aliment Pharmacol Ther, 1993 Apr, 7(2), 149 - 53
Two-week eradication regimen for metronidazole-resistant Helicobacter pylori; Logan RP et al.; At present there is no generally accepted treatment regimen for eradicating metronidazole-resistant Helicobacter pylori . This study determines the eradication rate after treatment with 40 mg omeprazole o.m . and 500 mg amoxycillin q.d.s . for 14 days, with 120 mg tripotassium dicitrato bismuthate q.d.s . for the first week (Days 1-7) and 750 mg ciprofloxacin b.d . for the second week (Days 8-14) . Thirty patients (16 male, mean age 45 years, range 16-80 years) with duodenal ulcers (n = 18) or non-ulcer dyspepsia (n = 2) and metronidazole-resistant H . pylori detected by histology, culture, in vitro sensitivity tests and a positive 13C-urea breath test entered the study . Follow-up was by 13C-urea breath test at the end of treatment and at 1, 3, 6, and 12 months . Eradication was defined as a negative 13C-urea breath test at least 1 month after finishing treatment . H . pylori was successfully eradicated in 21/30 (71%) patients (median follow-up 10.2 months, range 4-12 months) . A pre-treatment ciprofloxacin-resistant strain was isolated in 1/9 patients in whom eradication failed . Of 30 patients 29 completed the 2-week regimen; one patient experienced dizziness after 3 days of treatment . The most common side-effect was increased stool frequency (n = 6) . This 2-week treatment regimen for metronidazole-resistant H . pylori is well tolerated and achieves an eradication rate of 70%.

Br J Clin Pharmacol, 1993 Mar, 35(3), 302 - 4
The influence of chronic administration of calcium carbonate on the bioavailability of oral ciprofloxacin; Sahai J et al.; Six healthy male volunteers participated in a two-period, two-treatment study to determine the effect of chronic calcium carbonate administration on ciprofloxacin bioavailability . There was a mean reduction of 40% in Cmax and 43% in AUC when calcium carbonate was administered with ciprofloxacin, compared with ciprofloxacin alone (P < 0.05) . There were no changes in either half-life or tmax . It is therefore recommended that patients being treated with ciprofloxacin for serious infections refrain from ingesting calcium supplements . If this is not possible, administration of ciprofloxacin 2 h before ingestion of the supplement is suggested.

Clin Pharmacol Ther, 1993 Mar, 53(3), 292 - 7
Cations in the didanosine tablet reduce ciprofloxacin bioavailability; Sahai J et al.; The effect of the magnesium-aluminum cations contained in didanosine chewable tablets on ciprofloxacin pharmacokinetics was evaluated in 12 healthy volunteers . The study was designed as a randomized, balanced, open, two-period, two-treatment crossover trial with a 7-day washout period between treatments . In one phase, subjects received a single 750 mg ciprofloxacin tablet alone . In the didanosinecation regimen, subjects received two didanosine-placebo tablets every 12 hours for two doses . On day 2, they received two didanosine-placebo tablets immediately followed by a single 750 mg ciprofloxacin tablet . Serial blood samples were collected for 24 hours after administration of each ciprofloxacin dose . The average maximum concentration of ciprofloxacin alone was 3.38 +/- 0.63 (SD) micrograms/ml compared with 0.25 +/- 0.21 (SD) micrograms/ml when ciprofloxacin was administered with the didanosine placebo (p < 0.0001) . The mean (+/- SD) area under the plasma drug concentration-time curve from time 0 to the last measurable concentration for ciprofloxacin alone was 15.50 +/- 2.69 micrograms.hr/ml compared with 0.26 +/- 0.21 micrograms.hr/ml when ciprofloxacin was coadministered with the didanosine-placebo (p < 0.0001) . The mean time to maximum concentration of ciprofloxacin alone decreased from 1.56 +/- 0.62 to 0.75 +/- 0.38 hours with buffer administration (p = 0.0012) . The simultaneous administration of ciprofloxacin and didanosine should be avoided.

Ann Pharmacother, 1993 Mar, 27(3), 302 - 3
Arthropathy secondary to ciprofloxacin in an adult cystic fibrosis patient; Samuelson WM et al.; OBJECTIVE: To report a case of possible ciprofloxacin-induced arthropathy in an adult patient with cystic fibrosis (CF) . CASE SUMMARY: A 25-year-old man with CF received three separate courses of ciprofloxacin therapy at usual doses for acute pulmonary exacerbations of his disease . During the second and third courses, the patient experienced bilateral swelling of his knees between two to three weeks after initiation of each course . Both times symptoms markedly decreased after discontinuation of the drug . The patient had no prior history of arthropathy . Furthermore, during the last two acute exacerbations of his CF, he did not receive ciprofloxacin and did not experience any symptoms of arthropathy . DISCUSSION: Prior cases of quinolone-induced arthropathy involving pediatric CF patients or adult patients without CF have been reported in the literature . We report the first case of such an arthropathy in an adult patient with CF . The findings are supported by a rechallenge with the drug . CONCLUSIONS: It is likely that ciprofloxacin may produce arthropathy in adult as well as pediatric patients with CF . Quinolones should be considered as a possible cause of arthropathy in adult CF patients.

J Antimicrob Chemother, 1993 Feb, 31(2), 281 - 7
Rapid fluorometric measurement of the intra-cellular concentration of ciprofloxacin in mouse peritoneal macrophages; Chateau MT et al.; A simple fluorometric assay requiring only a single sample of cells to determine the number of cells, from the DNA linked to the fluorochrome 4',6-diamidino-2-phenylindol (DAPI), and the uptake of ciprofloxacin, a natural fluorescent quinolone is described . Mouse peritoneal macrophages were found to concentrate ciprofloxacin up to 12.7 (+/- 1.5)-fold . Combined fluorometry provides a precise, sensitive method for determining the intracellular concentration of fluoroquinolones, as well as that of naturally fluorescent or fluorochrome-linked drugs.

FEMS Microbiol Lett, 1993 Jan 15, 106(2), 187 - 91
Quinolone action in Escherichia coli cells carrying gyrA and gyrB mutations; Herrera G et al.; We have isolated spontaneous mutant strains of Escherichia coli KL16 showing different levels of nalidixic acid (NAL) resistance . From 40 independent mutants, 36 had gyrA and four had gyrB mutations . Most of the gyrA mutations (30/36) conferred high level NAL resistance . In contrast, the only gyrB mutation that conferred a relatively high level of NAL resistance also determined enhanced susceptibility to quinolones with a piperazinyl substituent at C7 position of the quinolone ring (amphoteric quinolones) . This gyrB mutation (denoted gyrB1604), jointly with a gyrA mutation (denoted gyrA972) which confers a high level of quinolone resistance, were used to construct strain IC2476, carrying the two gyr mutant alleles . The susceptibility of this strain to amphoteric quinolones (pipemidic acid, norfloxacin and ciprofloxacin) was similar to that of the gyrA972 single mutant . This result indicates that the change in GyrA subunit which determines a high level of quinolone-resistance has the capacity to mask the hypersusceptibility to amphoteric quinolones promoted by the GyrB1604 mutant subunit . This capacity was further confirmed by studying the effects of ciprofloxacin (CFX) on gyrase inhibition in the gyrA972 gyrB1604 strain.

Eur J Clin Pharmacol, 1993, 44(4), 365 - 7
The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam in healthy volunteers; Kamali F et al.; The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study . Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml.h-1 kg-1; with ciprofloxacin: 12.3 ml.h-1 kg-1) . Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l.kg-1; with ciprofloxacin: 1.1 l.kg-1) . However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.

Cytometry, 1993, 14(3), 281 - 6
Multiparameter flow cytometric analysis of a novel cytotoxin (factor 2) induced tumor cell membrane permeability; Ni J et al.; An improved twin-probe multiparameter flow cytometric technique was applied to examine a novel cytotoxin, Factor (F2), induced tumor cell permeability . Ability to retain preloaded intracellular bis-carboxyethyl carboxyfluorescein (BCECF, green fluorescence) and to exclude extracellular propidium (red fluorescence) was measured simultaneously with forward and right-angle scatter . In addition to the two expected cell populations which were stained green negative, red positive ("membrane-damaged" and "non-viable", Region 2), and green positive, red negative ("membrane intact" and "viable", Region 3), a third population was seen which fluoresced neither green nor red and displayed intermediate light scatter characteristics (Region 1) . K562 cells progressed from Region 3 to Region 1, and then from Region 1 to Region 2 after treatment with F2 . These results suggest that sequential changes in membrane structure lead to increased permeability, first with respect to intracellular BCECF and then in turn to extracellular propidium . Flow cytometric changes caused by F2 were detectable 10 min after treatment with 2.5 U/ml of F2, and 5 min after 10 or 40 U/ml of F2 . Flow cytometric analysis showed that F2-induced tumor cell lysis and growth inhibition were accompanied by rapid alternations in tumor cell membrane permeability . Flow cytometric analysis also distinguished F2 cytotoxicity from phorbol myristate acetate (PMA) associated cytotoxicity to K562 cells and determined that F2 produced spontaneously or induced by PMA and/or ciprofloxacin had a similar ability to induce tumor cell membrane permeability change.

J Orthop Trauma, 1993, 7(2), 142 - 5
Mycobacterium fortuitum osteomyelitis following trauma; Goodhart GL; Consequent to a high-speed motor-vehicle accident, a patient developed Mycobacterium fortuitum osteomyelitis of an open fracture of his proximal humerus . The patient was treated with a single debridement, oral ciprofloxacin, and hyperbaric oxygen and is free of disease at 2 years.

Arzneimittelforschung, 1993 Jan, 43(1), 56 - 60
Pharmacological properties of a new fluoroquinolone on the central nervous system in rodents; Guiol C et al.; The pharmacological effects of the novel fluoroquinolone 7-(1R,4R-2,5-diazebicyclo{2.2.1}heptan-2-yl)-1-(1,1-dimethyl )ethyl-6-fluoro - 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (BMY-40062, CAS 116143-32-9) on central nervous system were investigated in mice and rats, in comparison in some cases with those of reference quinolones . BMY-40062 showed no effect on general behavior, spontaneous activity, body temperature and neuromuscular coordination in rats at the doses of 1000 and 250 mg/kg . None of the quinolones tested including BMY-40062 modified the seizures induced by bicuculline, a specific GABA A antagonist . BMY-40062 and ciprofloxacin did not consistently influence the pentetrazol-induced convulsions . On the contrary, pefloxacin exhibited a marked convulsivant activity . In the fenbufen (non-steroidal anti-inflammatory drug)-induced seizure model, BMY-40062 showed no effect . Enoxacin, norfloxacin followed by ciprofloxacin elicited a convulsivant effect in presence of fenbufen . Under these experimental conditions, BMY-40062 had no effect on the central nervous system compared to the other tested quinolones in rodents.

Eur J Clin Pharmacol, 1993, 44(1), 101 - 2
The penetration of ciprofloxacin into bronchial mucosa, lung parenchyma, and pleural tissue after intravenous administration; Dan M et al.; We have studied the concentrations of ciprofloxacin in serum, bronchial mucosa, lung parenchyma, and pleural tissue after a single intravenous dose of 200 mg in 20 patients subjected to lung surgery . The concentrations of ciprofloxacin in the tissues exceeded that in the serum by 3-fold to 7-fold: serum 0.6 micrograms.ml-1, bronchial mucosa 1.9 micrograms.g-1, lung parenchyma 3.4 micrograms.g-, and pleural tissue 1.7 micrograms.g-1 . The achievable concentrations of ciprofloxacin in the tissues of the lower respiratory tract are above the MICs for most lung pathogens.

Int J Clin Pharmacol Res, 1993, 13(2), 81 - 5
Oral ciprofloxacin for treatment of severe infections; Lobo IM et al.; Twenty adult patients with severe infections were treated with oral ciprofloxacin, 500 or 750 mg twice daily . Treatment ranged from 8 to 25 days . Efficacy was good: 14 patients (70%) were cured, four (20%) improved and there were only two (10%) failures . Tolerance was very satisfactory, the most common side-effects being mild gastrointestinal symptoms (three patients) . Only one adverse laboratory result was observed: a transient rise in blood urea nitrogen and creatinine levels . None of the adverse effects led to discontinuation of treatment . Thus, ciprofloxacin presents as a promising drug for treatment of severe infections caused by susceptible organisms when ambulatorial therapy, at least during a large part of the treatment, is possible and desirable.

Tsitologiia, 1993, 35(8), 71 - 8
{The effect of Mycoplasma contamination and decontamination with ciprofloxacin on the karyotypic structure of the Chinese hamster V-79 lung cell line}; Polianskaia GG et al.; Karyotypic variability was investigated for the Chinese hamster lung cell line V-79, infected (contaminated) with a mycoplasma Acholeplasma laidlawii A . The mycoplasmal contamination did not affect cell distribution for the chromosome number . However, 30-70 days following cell culture contamination the increase in chromosomal aberrations was observed in the contaminated cell line primarily at the expense of chromosomal breaks . The following cyprofloxacin treatment of the culture resulted in mycoplasmal elimination and decrease in the frequency of chromosomal aberrations up to the control level . The analysis of G-banded chromosomes showed no significant differences in karyotypes of originally non-infected cells and cells after decontamination . The karyotypic variability, induced by mycoplasmal infection in V-79 cell line, differed from that in the muntjac skin fibroblast cell line, the latter being described elsewhere . A predominant type of chromosomal variability in V-79 cell line are chromosomal breaks, whereas in the muntjac fibroblast cell line dicentrics (telomeric fusions) were primarily observed, possible explanations of these differences being discussed . This may be presumably due to differences in karyotypic structure of these two cell lines, and to their different adaptation to culture conditions.

Eye, 1993, 7 ( Pt 4), 529 - 34
Infective endophthalmitis following vitreoretinal surgery; Bacon AS et al.; Eleven cases of endophthalmitis occurring after vitreoretinal surgery are described . At Moorfields Hospital, London, from 1986 to 1990 the incidence of endophthalmitis after explant surgery with or without drain was 0.19% and after vitrectomy was 0.15% . We conclude that the parity may be due to the intraocular instrumentation of most conventional retinal detachment repair procedures . The best indicator of poor prognosis was speed of onset of symptoms, those with rapid evolution having the worst outcome; 2 of these cases were enucleated . Those presenting at 2-3 days had the best outcome, consistent with infection due to a less virulent organism . Delays in diagnosis were in part due to the posterior location of signs of infection . Potential risk factors amenable to prophylactic strategy were identified in 10 of the 11 patients . Supplementary prophylaxis using ciprofloxacin or imipenem is proposed for cases with an identifiable risk factor . After systemic administration these antibiotics achieve vitreous levels that exceed the MIC90 of the commonest causative pathogens.

Ann Dermatol Venereol, 1993, 120(4), 289 - 92
{Mycobacterium kansasii cutaneous infection}; Delaporte E et al.; The authors report a case of cutaneous infection caused by Mycobacterium kansasii in an immunocompetent woman . The mycobacterium was identified after a search for mycolic acids and the species-specific phenol-glycolipid K1 . As minocycline followed by ciprofloxacin were ineffective, a conventional antituberculous treatment was prescribed and was fully successful.

Retina, 1993, 13(4), 326 - 30
Clearance and distribution of ciprofloxacin after intravitreal injection; Pearson PA et al.; This study was designed to determine the drug concentration and clearance after intravitreal injection of ciprofloxacin . Ciprofloxacin (100 micrograms/0.1 cc) was injected into the vitreous of normal eyes and into eyes that had undergone lensectomy and vitrectomy . Drug concentration was determined using high-pressure liquid chromatography analysis 0.5, 2, 4, and 12 hours after injection . In normal eyes, the elimination half life was 2.2 hours with a distribution volume of 1.2 ml . In aphakic vitrectomized eyes, the half life was 1 hour and the distribution volume was 1.4 ml . The majority of the drug appears to leave via a transretinal route, but clearance was not inhibited by probenecid . Because of the relatively short half life, intravitreal administration of ciprofloxacin for the treatment of endophthalmitis would provide only short-term therapy and would need to be supplemented by other forms of treatment.

Antibiot Khimioter, 1993 Jan, 38(1), 42 - 5
{Effectiveness of the new quinolones, ciprofloxacin and pefloxacin in experimental plague}; Kasatkina IV et al.; Efficacy of ciprofloxacin and pefloxacin in plague infection was studies on albino mice by comparison with that of nalidixic acid . The mice were contaminated subcutaneously . The treatment with the drugs was started 6 or 24 hours after the contamination . The MICs of ciprofloxacin, pefloxacin and nalidixic acid were 0.01 to 0.02, 0.15 and 1.25 to 2.5 micrograms/ml respectively . By the ED50 ciprofloxacin proved to be the most efficient . Pefloxacin was 6 times less efficient and nalidixic acid was 100 times less efficient . The quinolones were shown to be highly efficient when administered at 48-hour intervals.

Eur J Cancer, 1993, 29A(10), 1403 - 5
Granulocyte colony-stimulating factor (G-CSF) with or without a quinolone in the prevention of infection in cancer patients; Maiche AG et al.; 59 patients who had earlier developed an infection following antineoplastic chemotherapy were randomised to receive either granulocyte colony-stimulating factor (G-CSF) alone or G-CSF+quinolone as prophylaxis during subsequent identical chemotherapy courses . 30 patients received 48 courses of G+CSF, while 29 patients received 44 courses of G-CSF+ofloxacin or ciprofloxacin . The overall infection rate was 23% . Patients with WHO grade IV leukopenia at the onset of prophylactic treatment developed infection in 61% of cases when on G-CSF, but only in 22% when on G-CSF+quinolone (P = 0.002) . Patients with initial leukopenia of grade WHO III-I had only a 11% infection rate showing no significant difference between the treatment groups . The median duration of leukopenia < 1 x 10(9)/l was 4 days for patients receiving G-CSF alone and 3.5 days for those receiving additional quinolone . Patients developing infection had grade IV leukopenia for a median of 5 days . Both prophylactic treatments were well tolerated . We conclude that when prophylactic G-CSF is initiated at WHO grade IV leukopenia, addition of an oral quinolone reduces the risk of infection.

Drugs, 1993, 45 Suppl 3, 8 - 14
Quinolone mode of action--new aspects; Hooper DC; The interactions of quinolones with the complex of DNA gyrase and DNA have been elucidated by the sequencing of additional mutant gyrA and gyrB genes that produce altered quinolone susceptibility . Strong patterns have emerged in Escherichia coli in which amino acids between positions 67 and 106 of the gyrase A subunit (GyrA) and at positions 426 and 447 of the gyrase B subunit (GyrB) have been consistently identified as important for quinolone action . The susceptibility patterns and changes in amino acids 426 and 447 in mutant resistant GyrB proteins suggest direct electrostatic interactions with quinolones at these positions . The small size and the polar nature of the serine at position 83 of the E . coli GyrA protein are particularly important for determining enzyme sensitivity and bacterial susceptibility to quinolones . Norfloxacin and ciprofloxacin bind most stably to a complex of DNA gyrase and DNA rather than to either component alone, and reduction of norfloxacin binding to complexes containing resistant GyrA proteins confirms the biological relevance of this direct measure of quinolone interaction with the gyrase-DNA complex . Although recent crystallographic studies have expanded and refine information about gyrase structure at the atomic level, direct determination of the sites of quinolone binding within the gyrase-DNA complex awaits further studies . Although quinolones have little activity against E . coli topoisomerases I and III, topoisomerase IV, a recently described enzyme thought to be involved in chromosome segregation into daughter cells, has homology with GyrA and GyrB, particularly in regions important for quinolone action, and is inhibited by some quinolones in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Drugs, 1993, 45 Suppl 3, 65 - 72
Fluoroquinolones: interaction profile during enteral absorption; Deppermann KM et al.; Fluoroquinolones are used worldwide in the treatment of severe infections . These drugs, however, can interact with other agents . This paper is a review of drug interactions with different quinolone derivatives at the absorption phase; the review deals mainly with the prototype quinolones, ciprofloxacin and ofloxacin, and also with some of the newer agents . The concomitant agents considered are food, H2-receptor antagonists, anticholinergic drugs and metallic cation-containing compounds . Food (standard breakfast), H2-receptor antagonists and anticholinergic drugs had no major effect on the bioavailability of the quinolones . However, antacids, ferrous sulfate and other metallic cation-containing compounds impaired the bioavailability of the quinolones . This effect is due to chelation between the functional groups of the quinolone molecule and the metallic cations, resulting in insoluble complexes that can be absorbed . The degree of impairment varied between different quinolone derivatives.

Drugs, 1993, 45 Suppl 3, 46 - 53
Postmarketing surveillance of quinolones, 1990 to 1992; Davey P et al.; During the last 2 years, the major event in the postmarketing surveillance of quinolones has been the worldwide withdrawal of temafloxacin after only 15 weeks on the USA market . The Adverse Drug Reaction (ADR) reports that led to the withdrawal have been reviewed and show that the frequency and type of ADR and serious ADR were highly unusual in comparison with other quinolones marketed in the USA (ciprofloxacin, norfloxacin and ofloxacin) . The difficulty in establishing causality between drugs and ADRs is discussed . Prescription event monitoring and computerised databases are beginning to reach the size required to pick up rare ADRs but, even so, they can only establish association rather than causality . Perhaps a more important question is the issue of acceptable risk . This requires better definition in order to apply decision analysis to the options available for the treatment of bacterial infections.

Antimicrob Agents Chemother, 1992 Dec, 36(12), 2808 - 15
Efficacies of liposome-encapsulated streptomycin and ciprofloxacin against Mycobacterium avium-M . intracellulare complex infections in human peripheral blood monocyte/macrophages; Majumdar S et al.; Current treatments of disseminated infection caused by the Mycobacterium avium-M . intracellulare complex (MAC) are generally ineffective . Liposome-mediated delivery of antibiotics to MAC-infected tissues in vivo can enhance the efficacy of the drugs (N . Duzgunes, V . K . Perumal, L . Kesavalu, J . A . Goldstein, R . J . Debs, and P . R . J . Gangadharam, Antimicrob . Agents Chemother . 32:1404-1411, 1988; N . Duzgunes, D . A . Ashtekar, D . L . Flasher, N . Ghori, R . J . Debs, D . S . Friend, and P . R . J . Gangadharam, J . Infect . Dis . 164:143-151, 1991) . We investigated the therapeutic efficacies of liposome-encapsulated streptomycin and ciprofloxacin against growth of the MAC inside human peripheral blood monocyte/macrophages . Treatment was initiated 24 h after infection of macrophages with the MAC and stopped after 20 h, and the cells were incubated for another 7 days . The antimycobacterial activity of streptomycin was enhanced when the drug was delivered to macrophages in liposome-encapsulated form, reducing the CFU about threefold more than the free drug did throughout the concentration range studied (10 to 50 micrograms/ml) . With 50 micrograms of encapsulated streptomycin per ml, the CFU were reduced to 11% of the initial level of infection . Liposome-encapsulated ciprofloxacin was at least 50 times more effective against the intracellular bacteria than was the free drug: at a concentration of 0.1 microgram/ml, liposome-encapsulated ciprofloxacin had greater antimycobacterial activity than the free drug at 5 microgram/ml . With liposome-encapsulated ciprofloxacin at 5 micrograms/ml, the CFU were reduced by more than 1,000-fold at the end of the 7-day incubation period, compared with untreated controls . These results suggest that liposome-encapsulated ciprofloxacin or other fluoroquinolones may be effective against MAC infections in vivo.

Zentralbl Bakteriol, 1992 Dec, 277(4), 474 - 84
Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs?
Rastogi N, Goh KS, Guillou N, Labrousse V.
The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method . All the species tested were resistant to isoniazid and pyrazinamide . In general, clofazimine and D-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M . chelonei which were resistant to both drugs, and the M . szulgai and M . terrae complex which was resistant to D-cycloserine . The next broad-spectrum drug was ethionamide, followed by ansamycin, rifampin, capreomycin, kanamycin, streptomycin and ethambutol . Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M . xenopi, M . gordonae and M . fortuitum whereas M . kansasii and M . gastri were sensitive to ofloxacin only . When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M . kansasii, M . gastri and M . xenopi; 6/13 for M . gordonae; 5/13 for M . marinum; 3/13 for M . szulgai; 2/13 for M . fortuitum; 1/13 for the M . avium, M . scrofulaceum, M . simiae, and M . terrae complex, and none of the 13 in the case of M . chelonei . These results are discussed in relation to the multiple drug resistance of atypical mycobacteria . We conclude that the critical concentrations of drugs established for M . tuberculosis are not appropriate for atypical mycobacteria.

Kekkaku, 1992 Nov, 67(11), 735 - 8
{In vitro susceptibilities of Mycobacterium avium and Mycobacterium intracellulare to new macrolides, new quinolones, and antituberculous drugs on Dubos agar medium}; Ogawa K et al.; Mycobacterium avium and M . intracellulare were isolated from the sputum of patients infected with atypical mycobacteria using 1% Ogawa medium and identified by the DNA probe test . Then the MICs of various kinds of drugs against these mycobacterial species were determined on Dubos agar medium, and the drug susceptibilities were also determined on 1% Ogawa medium in parallel . The drugs tested were new macrolides, such as clarithromycin (CAM) and roxithromycin (RXM), new quinolones, such as ofloxacin (OFLX) and ciprofloxacin (CPFX), and antituberculous drugs, such as isoniazid (INH), rifampicin (PFP), streptomycin (SM), and ethambutol (EB) . The MICs of the drugs tested, especially those of CAM, OFLX, and RFP, when determined on Dubos agar medium, were generally lower against M . intracellulare than against M . avium . The susceptibilities of the mycobacterial isolates tested to RFP and SM determined on Dubos agar medium were markedly different from those determined on 1% Ogawa medium . Such discrepancies may be accounted for by absorption of these drugs to the egg medium and instability of RFP in the egg medium . Overall, our results indicate that the new macrolides and new quinolones are effective against atypical mycobacteria.

J Infect, 1992 Nov, 25(3), 267 - 71
A 7-day course of ciprofloxacin for enteric fever; Chew SK et al.; A prospective, open and non-randomised clinical trial using a 7-day short course of oral ciprofloxacin 500 mg twice daily was conducted on 25 adult patients with bacteraemic enteric fever . Twenty-four patients (96%) were cured and there was one treatment failure . Two patients with typhoid fever relapsed 6 weeks after finishing treatment . Defervescence of fever was rapid (median: 4 days) and the duration of hospitalisation was short (median: 8 days) . Both factors resulted in patient satisfaction . A short-course regime of ciprofloxacin for the treatment of enteric fever, is therefore, highly promisingPublication Types:

Clinical Trial

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