Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling.

Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.

Penetration of 0.3% ciprofloxacin, 0.3% ofloxacin, and 0.5% moxifloxacin into the cornea and aqueous humor of enucleated human eyes.

We aimed to quantify the penetration of ciprofloxacin, ofloxacin, and moxifloxacin into the cornea and aqueous humor of cadaver eyes. A total of 60 enucleated eyes, not eligible for corneal transplantation, were divided into three groups and immersed in commercial solutions of 0.3% ciprofloxacin, 0.3% ofloxacin, or 0.5% moxifloxacin for 10 min. Whole corneas and samples of aqueous humor were then harvested and frozen, and drug concentrations analyzed by liquid chromatography tandem mass spectrometry. The mean corneal concentration of moxifloxacin was twice as high as ofloxacin, and the latter was twice as high as ciprofloxacin. The mean concentration of moxifloxacin in the aqueous humor was four times higher than the other antibiotics, and the mean concentrations of ciprofloxacin and ofloxacin were statistically similar. The amount of drug that penetrated the anterior chamber after a 10-min immersion was far below the safe limit of endothelial toxicity of each preparation. Moxifloxacin demonstrated far superior penetration into the cornea and anterior chamber of cadaver eyes compared to ciprofloxacin and ofloxacin. One should not expect endothelial toxicity with the commercial eye drops of ciprofloxacin, ofloxacin, and moxifloxacin that reach the anterior chamber through the cornea.

Penetration of 0. 3% ciprofloxacin, 0. 3% ofloxacin, and 0. 5% moxifloxacin into the cornea and aqueous humor of enucleated human eyes

We aimed to quantify the penetration of ciprofloxacin, ofloxacin, and moxifloxacin into the cornea and aqueous humor of cadaver eyes. A total of 60 enucleated eyes, not eligible for corneal transplantation, were divided into three groups and immersed in commercial solutions of 0.3% ciprofloxacin, 0.3% ofloxacin, or 0.5% moxifloxacin for 10 min. Whole corneas and samples of aqueous humor were then harvested and frozen, and drug concentrations analyzed by liquid chromatography tandem mass spectrometry. The mean corneal concentration of moxifloxacin was twice as high as ofloxacin, and the latter was twice as high as ciprofloxacin. The mean concentration of moxifloxacin in the aqueous humor was four times higher than the other antibiotics, and the mean concentrations of ciprofloxacin and ofloxacin were statistically similar. The amount of drug that penetrated the anterior chamber after a 10-min immersion was far below the safe limit of endothelial toxicity of each preparation. Moxifloxacin demonstrated far superior penetration into the cornea and anterior chamber of cadaver eyes compared to ciprofloxacin and ofloxacin. One should not expect endothelial toxicity with the commercial eye drops of ciprofloxacin, ofloxacin, and moxifloxacin that reach the anterior chamber through the cornea.

Development and evaluation of bilayer tablets of combination of antibiotics for the treatment of sexually transmitted disease

ABSTRACT The present research work was envisaged to develop bilayer tablets to improve therapeutic efficacy of antibiotic combination for the treatment of sexually transmitted diseases. The combination of two antibiotics i.e. cefixime trihydrate and ofloxacin were used for the preparation of bilayer tablets which act against genito-urinary infections. The formulations comprise of cefixime trihydrate as immediate release layer formulated using different superdisintegrants and ofloxacin as extended release layer containing HPMC K100M. Evaluation of bilayer tablets were performed for the immediate release cefixime layer and sustain release ofloxacin layer with optimization of excipients. The immediate release layer of cefixime showed complete release within 30 min and ofloxacin release was extended up to 24 hours. The similarity factor value of ofloxacin sustained release layer was found to be 87.01 for initial and 80.35 after 3 months stability when compared with marketed reference product. The present study revealed that cefixime trihydrate and ofloxacin bilayer tablets were successfully developed for the use against sexually transmitted infections.

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: III. fluoroquinolones.

This review is the third installment in a comprehensive State of the Art series and aims to evaluate the use of fluoroquinolones in the management of P. aeruginosa infection in both children and adults with cystic fibrosis (CF). Oral and intravenous ciprofloxacin have been shown to be well-tolerated in the treatment of acute pulmonary exacerbations (APE) secondary to P. aeruginosa. Older literature supports an oral dosing regimen of 40 mg/kg/day divided every 12 hr, up to 2 g/day, and intravenous (IV) ciprofloxacin 30 mg/kg/day divided every 8 hr, maximum 1.2 g/day in children, and 750 mg administered orally twice a day or 400 mg IV every 8 hr in adults. However, a recent pharmacodynamic (PD) modeling study shows that the literature, U.S. Food and Drug Administration (FDA)-approved, and Cystic Fibrosis Foundation (CFF) guideline dosing regimens may be suboptimal for the treatment of P. aeruginosa in APE. Further study is warranted to determine if higher doses of ciprofloxacin are needed. Limited pharmacokinetic (PK), PK/PD, and efficacy studies involving levofloxacin exist in adult patients with CF. No pediatric data exists for levofloxacin in CF patients. Further study is needed to determine the tolerability and efficacy of levofloxacin in APE. At this time, the routine use of levofloxacin in the treatment of APE in pediatric and adult patients cannot be recommended.

MP-376 (Aeroquin) for chronic Pseudomonas aeruginosa infections.

INTRODUCTION: The chronic airway infection with Pseudomonas aeruginosa (PA) is a risk factor for rapid disease progression in various chronic pulmonary diseases including cystic fibrosis or chronic obstructive pulmonary disease. Inhaled antibiotics are able to treat effectively such chronic airway infections, and MP-376 is currently in late-stage clinical development for such an indication. AREAS COVERED: Review of the existing preclinical and clinical data on MP-376, with a focus on the efficacy and safety of the compound on chronic airways infections due to PA. EXPERT OPINION: Chronic airways infection with PA represents a therapeutic challenge because of its own complex mechanisms of defense, because of the rapid development of antibiotic resistance and by the fact that systemic antibiotics are not always able to achieve appropriate concentrations at lung level. Inhaled antibiotics (tobramycin, aztreonam, etc.) represent optimal alternatives to their systemic homologs due to their better penetrability in the lungs and due to the lower systemic exposure. Inhaled levofloxacin which is currently investigated for chronic airways infection might be another possible antipseudomonal inhaled therapy.

Validation studies on blood collection from the jugular vein of conscious mice.

A method for blood collection from the jugular vein of mice without anesthesia was compared with a tail-incision technique. Jugular vein blood collection allowed withdrawal of almost 15% of the circulating blood volume at a time in less than 1 min. Hemolysis, hematocrit, and plasma thrombin-antithrombin complexes (a marker of blood coagulation) were higher in samples collected from the tail vein than the jugular vein. Mice produced similar plasma corticosterone levels after serial blood collection by either method. Tail incision led to a slight but significant increase in C-reactive protein levels. Using the jugular venipuncture technique, we then performed a pharmacokinetic study and an oral glucose tolerance test. Plasma concentrations of levofloxacin, an antimicrobial agent, were dose-dependently elevated after oral administration, and linear increases in C(max) and AUC were observed. We also confirmed that overall glucose excursion is significantly decreased in mice treated with exendin 4, a glucagon-like peptide 1 agonist. These results indicate that the jugular venipuncture is a useful technique from the point of view of no requirement for anesthetics, serial blood collection at short intervals, large volume of blood collection, quality of sample and animal welfare. This technique is of particular interest for studies that examine time-dependent changes in blood variables.

Comparison of corneal and aqueous humor penetration of moxifloxacin, gatifloxacin and levofloxacin during keratoplasty.

INTRODUCTION: Achieving high antibiotic concentrations is important for preventing and treating postoperative infections. However, no study has simultaneously compared the achieved concentrations of moxifloxacin, gatifloxacin, and levofloxacin in the human cornea and aqueous humor. The authors therefore performed a randomized study to determine the concentrations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin in the corneal tissue and aqueous humor after topical instillation in patients undergoing penetrating keratoplasty. METHODS: Patients who required penetrating keratoplasty were eligible for this study. The topical preparations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin used in the study were preservative free (Japanese formulations). Patients were randomly assigned to one of three sequential drug groups, in which each drug was administered three times before surgery. In each administration cycle, the patients received two drops of each drug at 2-minute intervals. Samples of corneal tissue and aqueous humor were collected during surgery. The concentrations of each drug in the samples were determined by high-performance liquid chromatography. RESULTS: A total of 63 patients across eight centers in Japan were enrolled in the study. Overall, 61 corneal and 58 aqueous humor samples were evaluated. The concentration (mean±standard deviation) of moxifloxacin in corneal tissues was 12.66±8.93 µg/g, which was significantly higher than that of gatifloxacin (4.71±3.39 µg/g; P<0.0001) and levofloxacin (5.95±4.02 µg/g; P<0.0001). The mean concentration of moxifloxacin in aqueous humor samples was 1.40±1.17 µg/mL, which was significantly higher than that of gatifloxacin (0.65±0.80 µg/mL; P=0.0001) and levofloxacin (0.89±0.86 µg/mL; P<0.05). The sequence of drug administration did not significantly affect the results. CONCLUSION: These results show that 0.5% moxifloxacin achieved superior ocular concentration than both 0.3% gatifloxacin and 0.5% levofloxacin.

Bronchopulmonary pharmacokinetic and pharmacodynamic profiles of levofloxacin 750 mg once daily in adults undergoing treatment for acute exacerbation of chronic bronchitis.

While previous reports have described the bronchopulmonary profile of the fluoroquinolones in healthy volunteers, limited data are available in infected patients. The purpose of this study was to determine the intrapulmonary profile of high-dose (750 mg) levofloxacin in patients during an acute exacerbation of chronic bronchitis (AECB). Twenty-four patients experiencing clinical signs and symptoms of AECB were enrolled. Once enrolled, patients received levofloxacin 750 mg once daily × 5 days. Bronchoalveolar lavage aspirates and simultaneous plasma samples were obtained at 4 h, 12 h or 24 h after the third dose. Concentrations in biologic matrixes were determined with a validated HPLC method. Epithelial lining fluid (ELF) concentrations were calculated using the urea dilution method. Five patients did not complete the trial, 19 patients underwent bronchoscopy, 18 (52 ± 13 yrs) had sufficient samples for analysis and confirmed medication compliance. Mean plasma concentrations at 4, 12, and 24 h were 8.0 ± 2.5, 5.8 ± 1.2, and 2.2 ± 1.2 µg/mL. Mean ELF values at 4, 12, and 24 h were 7.5 ± 3.0, 8.3 ± 6.0, and 1.2 ± 0.9 µg/mL. Mean alveolar macrophage (AM) concentrations at 4, 12, and 24 h were 38.5 ± 43.7, 13.4 ± 14.4, and 9.0 ± 7.5 µg/mL. The penetration (ELF/plasma ratio) into the infection site was 113%. In these subjects with AECB, levofloxacin 750 mg once daily reached adequate exposures in the plasma, ELF, and AMs for the most commonly associated pathogens.

[Hydrogelexpander as drug delivery system for antibiotics]. / Hydrogelexpander als Medikamentenabgabe-System für Antibiotika.

PURPOSE: The suitability of a high-hydrophilic osmotic self-inflating hydrogel expander consisting of a co-polymer of N-vinylpyrolidone and methyl methacrylate as a drug delivery system for antibiotics to prevent a postoperative infection was investigated in a laboratory setting. METHODS: The dry expanders were incubated in a 0.3 % solution of Ofloxacin or Tobramycin for 24 hours. The completely swollen expander had increased in volume from 0.3 mL to almost 3 mL (adsorbing 2.7 mL of the 0.3 % solution, i. e.,8.1 mg of Ofloxacin or Tobramycin, respectively). Addressing the elimination of both antibiotics, the concentrations in 15 mL elution medium (simulating the volume of the orbit in a newborn baby) were measured after 0.25, 1, 2, 6, 24, 48 and 72 hours of elution. 0.9 % sodium chloride (B. Braun Melsungen, Germany) was used as elution medium. To imitate fluid exchange due to blood perfusion in the surrounding tissue the medium was renewed after every sampling. For each substance 10 expanders were tested. Concentrations of antibiotic were determined by HPLC/UV for Ofloxacin and by using a specific fluorescence-polarisation immunoassay (Abbott TDx) for Tobramycin. RESULTS: Mean concentrations of Ofloxacin at 0.25, 1, 2, 6, 24, 48 and 72 hours after beginning of the elution were 50.2, 46.8, 41.2, 75.4, 88.2, 46.2 and 19.1 µg/mL, respectively. The cumulative amount of Ofloxacin eluted after 72 hours reached 68 % of the loading dose. The corresponding mean concentrations of Tobramycin were 38.8, 48.5, 40.5, 69.8, 88.7, 119.3 and 71.6 µg/mL. The cumulative eluted amount was 88 %. CONCLUSIONS: The investigated hydrogel expanders soaked in 0.3 % antibiotic solution can store and later on release sufficient amounts of Ofloxacin or Tobramycin to produce antimicrobial effective concentrations in vitro in the surrounding environment. This principle, when used in a clinical setting, might help to eliminate post-implantation infection which is one of the major complications in clinical use.

Failure of fluorescence to reveal middle ear penetration of quinolone drops.

OBJECTIVE: To evaluate the utility of fluorescence to assess penetration of quinolone ear drops (EDs) through tympanostomy tubes (TTs), the middle ear, eustachian tube, and into the oropharynx. DESIGN: Before-and-after trial. SETTING: Academic, tertiary care hospital. PATIENTS: Young children undergoing TT placement for otitis media and adolescents or adults undergoing repair of tympanic membrane (TM) perforations were included. INTERVENTIONS: Fluorescence of ofloxacin otic solution and serial dilutions was assessed with a Wood's lamp in vitro. Passage of ototopically administered ofloxacin into the pharynx was assessed in patients at the time of TT placement or TM repair. The oropharynx was visualized for fluorescence with a UV light for up to 2 hours after otic instillation. MAIN OUTCOME MEASURE: Oropharyngeal fluorescence. RESULTS: Ofloxacin otic fluorescence was visible at up to a 1:4 dilution. Fluorescence was confirmed in vivo by placing 1 drop of ofloxacin into the posterior pharynx and visualizing it transorally. Fluorescence was not identified in any of 20 patients after TT placement and in any of 6 patients prior to tympanoplasty. Two patients undergoing tympanoplasty reported tasting the EDs. CONCLUSION: Fluorescence is not a satisfactory method of assessing quinolone ED penetration through TTs and TM perforations, the middle ear, and into the nasopharynx.

Efficient penetration into aqueous humor by administration of oral and topical levofloxacin.

PURPOSE: We investigated whether an optimized combination of oral and topical levofloxacin would lead to higher levofloxacin concentrations in aqueous humor. METHODS: Fifteen patients with cataracts in both eyes began topical treatment at 1 week before the first surgery and oral treatment at 1 day before the first surgery. On the day of surgery, they received oral and topical levofloxacin at 4 h and 1 h before surgery, respectively. Two days after the first operation, we performed cataract surgery on the second eye with the same drug administration protocol. RESULTS: Postsurgery concentrations of levofloxacin in the aqueous humor of the first and second eyes were 2.87±0.89 µg/mL (mean±standard deviation, n=15) and 3.76±1.32 µg/mL, respectively; the levofloxacin level in the second eye was significantly higher than that in the first eye (P=0.0085). CONCLUSIONS: Our protocol to achieve high aqueous humor concentrations of levofloxacin may be favorable in preventing endophthalmitis after eye surgery.

Pharmacokinetics and safety of MP-376 (levofloxacin inhalation solution) in cystic fibrosis subjects.

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (C(max)) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean C(max) for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin C(max) ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development.

Comparison of systemic and otic administration of ofloxacin.

OBJECTIVES: To assess the feasibility of delivering ofloxacin across the intact tympanic membrane; to compare middle ear bioavailability of ofloxacin after otic and systemic administrations; to determine distribution of otically delivered ofloxacin to other tissues. STUDY DESIGN: A prospective, controlled animal study. METHODS: Rats underwent surgery wherein the middle ear cavity was opened and filled with saline. An equivalent amount of ofloxacin was delivered intraperitoneally or into the external ear canal. Saline within the middle ear was sampled and completely replaced in 15-minute intervals for 3 hours. Blood was collected twice after the initial application of ofloxacin for high-performance liquid chromatography (HPLC). Animals were sacrificed 3 hours after the initial addition of ofloxacin; the temporal bones were harvested for histological analysis; urine and colon mucosa were collected for HPLC analysis. RESULTS: Both systemic and otic applications led to a comparable accumulation of ofloxacin in the middle ear over the 3-hour period after the initial administration. The pharmacokinetics of ofloxacin penetration into the middle ear was sporadic and subject-dependent. Both methods of administration led to drug accumulation in blood serum, urine, and colonic mucosa. CONCLUSIONS: Topical application of ofloxacin to the intact tympanic membrane allows for drug penetration into the middle ear space. Similar middle ear ofloxacin levels could be achieved with systemic and topic applications, but drug concentrations were inconsistent. The accumulation of ofloxacin in other tissues suggests applications designed to be ototopical may also result in systemic absorption.

Carrier-mediated uptake of Levofloxacin by BeWo cells, a human trophoblast cell line.

OBJECTIVE: Placental transfer of Levofloxacin (LF), a broad spectrum fluoroquinolone antibiotic, and its inhibition was investigated in BeWo cells, a human trophoblast cell line. METHODS: The experiments of LF uptake by BeWo cells were performed after preincubation and in the presence of the P-glycoprotein inhibitors (Cyclosporin A, Verapamil and Quercetin), the organic anion/cation transporter inhibitor (Cimetidine) and the MCT substrates (lactic acid and salicylic acid). RESULTS: P-glycoprotein inhibitors increased the uptake of LF by BeWo cells. The increase in LF accumulation by Cyclosporin A, Verapamil and Quercetin was by 30, 90 and 80%, respectively. Cimetidine, the organic cation inhibitor, increased the transport of LF by 48%. Lactic acid and salicylic acid, the MCT substrates, initially decreased the accumulation of LF by 30% and subsequently increased the uptake of LF by 500 and 53%, respectively. CONCLUSIONS: The uptake of LF by human trophoblast cells is mediated by multiple transporters as well as passive diffusion.

Efficacy of aerosol MP-376, a levofloxacin inhalation solution, in models of mouse lung infection due to Pseudomonas aeruginosa.

Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.

Increased anterior chamber penetration of topical levofloxacin 0.5% after pulsed dosing in cataract patients.

PURPOSE: This study aimed to investigate the rise in aqueous humour (AH) levels of levofloxacin after a specific perioperative pulsed topical drop regimen. METHODS: Thirty patients undergoing phacoemulsification surgery were administered two preoperative drops of levofloxacin 0.5%, 30 mins apart, and three pulsed drops postoperatively, 5 mins apart. Aqueous humour levels of levofloxacin were measured at the start of surgery and from 5 mins to 90 mins after the last postoperative drop. Samples from individual patients were collected at the time of surgery and at one additional sampling interval by aqueous tap, and analysed using a high-performance liquid chromatography assay. RESULTS: Aqueous humour levels of levofloxacin continued to rise gradually, reaching a mean peak level (C(max)) of 4.4 microg/ml (+/- 2.5) at 60 mins after the last postoperative drop was administered. This level exceeded the minimum inhibitory concentration of common ocular pathogens at least fourfold. At 90 mins after the last drop, mean AH levels remained > 3 microg/ml. CONCLUSIONS: This is the first study to measure AH levels of levofloxacin after postoperative pulsed dosing in humans. Higher AH levels were found than in previously reported studies in which only preoperative drops were given and levels were measured at the time of surgery. Levels of levofloxacin continued to rise for 60 mins after administration of the last postoperative drop, demonstrating that delivery and maintenance of effective antibiotic levels may be achievable with alternative dosing schedules.

Novel in vitro pharmacodynamic model simulating ofloxacin pharmacokinetics in the treatment of Pseudomonas aeruginosa biofilm-associated infections.

OBJECTIVES: The conventional in vitro models simulate pharmacodynamics of antibiotics in the treatment of planktonic Pseudomonas aeruginosa. In this study, we propose a novel pharmacodynamic model of ofloxacin activity in the treatment of P. aeruginosa biofilm. METHODS: P. aeruginosa biofilm carrying coupons were suspended in a continuous flow central compartment bioreactor (CCB). In the CCB, the pharmacokinetics of different ofloxacin dosing regimens were simulated. Samples from the coupons and the CCB were assessed for viability of the biofilm and the shedding planktonic cells, respectively, over 24h. In addition, ofloxacin concentrations were assessed in each sample withdrawn for the CCB using bioassay method. RESULTS: The microbiological outcomes on P. aeruginosa biofilm and the shedding planktonic cells in response to different ofloxacin dosing regimens were not parallel and this may explain the non-coincidence of microbiological and clinical outcomes with biofilm associated infections. CONCLUSION: The current study has introduced unprecedented novel dynamic model for the assessment of the microbiological outcome on both biofilm and shedding planktonic cells of P. aeruginosa in response to different dosing regimens of ofloxacin which in turn can simulate the clinical outcomes in biofilm associated infections of P. aeruginosa, e.g. cystic fibrosis. Furthermore, different scenarios of antibiotic dosing regimens against biofilm related infections can be mimicked using such model.

A comparison of fluoroquinolone penetration into human conjunctival tissue.

INTRODUCTION: Ocular penetration of newer fluoroquinolones (FQs) has not been fully investigated in humans, especially in regard to conjunctival tissue penetration. The aim of our study was to evaluate the conjunctival permeability of 3 FQs, which do not contain benzalkonium chloride, using excised pterygium tissue. METHODS: Patients undergoing pterygium surgery received a single application of one of the following: 0.5% moxifloxacin (MFLX), 0.3% gatifloxacin (GFLX), or 0.5% levofloxacin (LVFX). Samples of conjunctival tissue were collected 10, 30, or 45 min following administration of the study drug. Each sample was analyzed by high-performance liquid chromatography, and drug concentrations were measured over time. RESULTS: Conjunctival concentration of all 3 FQs was highest 10 minutes after instillation, then gradually decreased. At all time points, MFLX showed the highest conjunctival concentrations among the 3 drugs. Mean MFLX concentrations were 116.7 +/- 28.9, 19.0 +/- 6.3, and 15.9 +/- 4.7 microg/g at 10, 30, and 45 min, respectively, and were statistically greater than GFLX or LVFX concentrations at 10 and 45 min. CONCLUSIONS: All tested FQs achieved peak concentrations within 10 min following administration. Initial peak concentrations of MFLX were greater than either GFLX or LVFX, and concentrations of MFLX remained highest among the 3 FQs throughout the 45-min time window.

Targeted drug delivery to bone: pharmacokinetic and pharmacological properties of acidic oligopeptide-tagged drugs.

Site-specific drug delivery to bone is considered to be achievable by utilizing acidic amino acid homopeptides. We found that fluorescence-labeled acidic amino acid (L-Asp or L-Glu) homopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged an enzyme, tissue-nonspecific alkaline phosphatase, to see whether this would improve the efficacy of enzyme replacement therapy. The L-Asp hexapeptide-tagged drugs, including the enzyme, were selectively delivered to bone in comparison with the untagged drugs. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug or enzyme from the acidic oligopeptide. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged estradiol and levofloxacin, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. The adverse effect of estradiol on the uterus was greatly reduced by conjugation to the hexapeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs and enzyme.