Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10 to 20% go on to develop posttreatment Lyme disease syndrome (PTLDS). The nature of PTLDS remains unknown, but currently approved antibiotics for the treatment of Lyme disease do not appear to impact these symptoms after they have developed. We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection. In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary-phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria. We found that peptidoglycan synthesis continues in stationary-phase cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary-phase culture of B. burgdorferi Examination of the action of antibiotics in severe combined immunodeficient (SCID) mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. In contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining the early use of more potent antibiotics on the development of PTLDS may be warranted.

The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.

Borrelia burgdorferi is the causative agent of Lyme disease, which affects an estimated 300,000 people annually in the United States. When treated early, the disease usually resolves, but when left untreated, it can result in symptoms such as arthritis and encephalopathy. Treatment of the late-stage disease may require multiple courses of antibiotic therapy. Given that antibiotic resistance has not been observed for B. burgdorferi, the reason for the recalcitrance of late-stage disease to antibiotics is unclear. In other chronic infections, the presence of drug-tolerant persisters has been linked to recalcitrance of the disease. In this study, we examined the ability of B. burgdorferi to form persisters. Killing growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from the exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary-phase cells but not persisters. Mitomycin C, an anticancer agent that forms adducts with DNA, killed persisters and eradicated growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and the antibiotic was added again. Four pulse doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture.

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent, which has potent activity against most Gram-negative and Gram-positive organisms. It is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis.

The aim of this study was to assess the clinical potential of a new gemifloxacin 200 mg intravenous formulation by comparing its pharmacokinetic characteristics with those of the branded Factive(®) gemifloxacin tablet.

A single-dose, open-label, randomized-sequence, two-period crossover study was performed with 17 healthy male volunteers. The two treatment periods were separated by a 1-week washout period. Blood samples were taken for up to 48 h post-dose. Plasma gemifloxacin concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. To calculate the pharmacokinetic parameters, noncompartmental analysis was performed. The two formulations were considered to be pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (intravenous/oral formulations) of the area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and the AUC from time zero to infinity (AUC∞) were within the standard bioequivalence range (0.8-1.25). Safety and tolerability were evaluated on the basis of physical examinations, vital signs, electrocardiograms, clinical laboratory tests and adverse event monitoring.

Seventeen subjects were enrolled, and 15 subjects completed the study. Sixteen subjects received intravenous 200 mg gemifloxacin and 15 received oral 320 mg gemifloxacin. The 15 subjects in the pharmacokinetic analysis set had a mean (standard deviation [SD]) age, height and weight of 27.2 (5.3) years, 173.5 (4.4) cm and 67.3 (7.4) kg, respectively. Both formulations had similar pharmacokinetic profiles. For the intravenous formulation, the mean (SD) AUClast, AUC∞ and maximum plasma concentration (C max) values were 9.12 (4.03) μg·h/mL, 9.26 (4.07) μg·h/mL and 2.90 (1.65) μg/mL, respectively, while these values for the oral formulation were 9.44 (3.34) μg·h/mL, 9.60 (3.49) μg·h/mL and 2.03 (0.95) μg/mL, respectively. For the intravenous and oral formulations, the median (range) time to reach C max (t max) values were 0.9 (0.7-1.0) and 1.0 (0.5-2.0) h, respectively. The mean relative bioavailability was 68.99 %. The 90 % CI of the ratios of the log-transformed values of AUClast and AUC∞ was 0.82-1.07. There were no serious adverse events. The intravenous and oral formulations were associated with treatment-emergent adverse event incidences of 63 % (10/16) and 13 % (2/15), respectively. After the intravenous formulation was administered, application site pain and paraesthesia were the most frequently reported adverse events (31 and 25 %, respectively). All adverse events resolved spontaneously without treatment.

Intravenous 200 mg and oral 320 mg formulations of gemifloxacin are equivalent in terms of AUC following a single dose in healthy male subjects.

Community-acquired lower respiratory tract infections (LRTIs) exert a growing clinical and financial burden on healthcare systems and employers. In addition, antimicrobial resistance among pathogens, such as Streptococcus pneumoniae, has compromised the use of commonly prescribed antimicrobial compounds. Newer fluoroquinolones have been developed to meet these emerging demands. Gemifloxacin is a potent, dual-acting fluoroquinolone with excellent activity against S. pneumoniae (MIC(90)0.03-0.06 microg/ml) including those strains demonstrating resistance to other classes of antibiotics. Gemifloxacin demonstrated excellent clinical success in community-acquired lower respiratory infections, has an acceptable safety profile, and is a cost-effective alternative in the management of LRTIs including those caused by resistant pathogens.

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in a double-blind, ascending-single-dose study involving 56 healthy subjects (48 males and 8 females) who were randomly assigned to 1 of 7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1,000, or 1,500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1,500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the electrocardiograms, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free area under the plasma concentration-time curve/MIC(90) ratios and free maximum nemonoxacin concentration/MIC(90) ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 1 to 2 h and 9 to 16 h, respectively. The oral clearance was approximately 0.22 liter/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin.

Respiratory tract infections (RTIs) form a substantial clinical and financial burden, with the increasing complication of antimicrobial resistance. This resistance may compromise the use of many empirically prescribed antimicrobials. The new respiratory fluoroquinolones have been developed to overcome this burgeoning resistance. This group includes gemifloxacin, an enhanced-affinity fluoroquinolone that has been approved for clinical use in several countries and is characterised as a potent dual-acting agent with excellent in vitro activity against Streptococcus pneumoniae (minimum inhibitory concentration for 90% of strains (MIC90)=0.03-0.06 microg/mL). Gemifloxacin given once daily for 5-7 days has been shown to be non-inferior to, or in some instances superior to, comparator agents for the treatment of common lower RTIs. Moreover, it is generally well tolerated and is as safe as many frequently empirically prescribed antimicrobials. In addition, studies have shown gemifloxacin to be a cost-effective agent for some lower RTIs.

Fluoroquinolones, including ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin, represent a major advance in the development of antimicrobial agents. They offer significant activity against Gram-negative pathogens, while more advanced generation fluoroquinolones including levofloxacin, gemifloxacin, and moxifloxacin are significantly active against Gram-positive (e.g., Streptococcus pneumoniae for some members of the class), typical, atypical, and anaerobic pathogens. Fluoroquinolones have a pharmacokinetic/pharmacodynamic profile that exhibits concentration-dependent killing and good oral absorption, allowing for once-daily dosing.

Review of data from fluoroquinolone studies, with an emphasis on the associated rare, but potentially clinically important, adverse events in specific patient populations. Review of clinical efficacy is included where relevant to the topic under discussion.

A literature search was conducted using terms including fluoroquinolones, moxifloxacin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, safety, adverse events, drug interactions, and pharmacokinetic parameters to identify literature providing information regarding the safety profile of specified fluoroquinolones in special patient populations (i.e., the elderly, patients with liver disease, kidney disease, glycemic disorder, those at risk for cardiovascular events). Although specific date criteria were not applied to the search, preference was given to more recent publications. Online databases searched include MEDLINE and EMBASE and relevant textbooks were utilized as well.

Fluoroquinolones, when used either as monotherapy or as combination therapy depending on their individual indications, attain adequate concentrations for treating infections in different target sites, including epithelial lining fluid, alveolar macrophages, skin, and gastrointestinal tissues. Overall, fluoroquinolones have predictable and mild-to-moderate adverse-event profiles and are generally well tolerated. Findings of this review are limited by the availability of publications and case reports.

Fluoroquinolones, are associated with rare, but clinically important, adverse events in special patient populations (including the elderly; those with hepatic, renal, or glycemic disorders; and those at risk for cardiovascular events). Recognition of differences in the clinical efficacy and safety profiles of fluoroquinolones in special patient populations should lead to better antimicrobial agent selection.

New respiratory fluoroquinolones (FQs), such as levofloxacin, offer many improved qualities over older agents, such as ciprofloxacin. These include retaining excellent Gram-negative bacilli activity, with improved Gram-positive activity. New FQ-like levofloxacin possesses greater bioavailabilty and a longer serum half-life compared with ciprofloxacin, allowing for once-daily dosing, which may improve patient adherence. The high bioavailability of levofloxacin allows for rapid step-down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve patient quality of life. Levofloxacin has been evaluated for the treatment of community-acquired pneumonia (CAP) in numerous randomized clinical trials. Most published studies have used the 500 mg dose, although more recent studies have investigated the 750 mg dose once daily. These trials demonstrate that levofloxacin is effective and safe for the treatment of CAP, displaying relatively mild adverse effects that are more or less comparable with ciprofloxacin. Levofloxacin has much to offer in terms of bacterial eradication, including for resistant respiratory pathogens. However, ciprofloxacin-resistant organisms are becoming more prevalent so prudence must be exercised when prescribing this agent.

Multidrug resistance associated protein (MRP) is a major family of efflux transporters involved in drug efflux leading to drug resistance. The objective of this study was to explore physical barriers for ocular drug absorption and to verify if the role of efflux transporters. MRP-2 is a major homologue of MRP family and found to express on the apical side of cell membrane. Cultured Rabbit Corneal Epithelial Cells (rCEC) were selected as an in vitro model for corneal epithelium. [14C]-erythromycin which is a proven substrate for MRP-2 was selected as a model drug for functional expression studies. MK-571, a known specific and potent inhibitor for MRP-2 was added to inhibit MRP mediated efflux. Membrane fraction of rCEC was used for western blot analysis. Polarized transport of [14C]-erythromycin was observed in rCEC and transport from B-->A was significantly high than from A-->B. Permeability's increased significantly from A-->B in the presence of MK-571 and ketoconozole. Uptake of [14C]-erythromycin in the presence of MK-571 was significantly higher than control in rCEC. RT-PCR analysis indicated a unique and distinct band at approximately 498 bp corresponding to MRP-2 in rCEC and MDCK11-MRP-2 cells. Immunoprecipitation followed by Western Blot analysis indicated a specific band at approximately 190 kDa in membrane fraction of rCEC and MDCK11-MRP-2 cells. For the first time we have demonstrated high expression of MRP-2 in rabbit corneal epithelium and its functional activity causing drug efflux. RT-PCR, immunoprecipitation followed by Western blot analysis further confirms the result.

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most gram-negative and gram-positive organisms, such as the important community-acquired respiratory pathogens Streptococcus pneumoniae (including multidrug-resistant S. pneumoniae), Haemophilus influenzae , and Moraxella catarrhalis . The agent's mechanism of action involves dual targeting of two essential bacterial enzymes: DNA gyrase and topoisomerase IV. Gemifloxacin was approved by the Food and Drug Administration in April 2003 for treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The drug has an oral bioavailability of approximately 71%. Approximately 20-35% of gemifloxacin is excreted unchanged in the urine after 24 hours. The elimination half-life of gemifloxacin is 6-8 hours in patients with normal renal function, supporting once-daily dosing. The 24-hour free-drug area under the plasma concentration-time curve:minimum inhibitory concentration ratio (fAUC(0-24):MIC) associated with efficacy, based on results from in vitro and animal models of infection, is approximately 30. With a mean fAUC(0-24) of approximately 3 microg*hour/ml (35% of total AUC(0-24) of 8.4) and a median S. pneumoniae MIC for 90% of tested strains of 0.03, a fAUC(0-24):MIC ratio of 100 would be expected after standard dosing (320 mg once/day). In clinical studies involving both hospitalized and outpatient populations, gemifloxacin has been highly effective in the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis. Clinical success rates ranged from 93.9-95.9% in patients with community-acquired pneumonia and 96.1-97.5% in those with acute exacerbation of chronic bronchitis. Gemifloxacin is well tolerated; the frequency of adverse events with this agent is low. Most adverse events are mild-to-moderate in severity, with diarrhea (< 4%), nausea and rash (< 3%), and headache (< 2%) most commonly reported. Drug interactions with gemifloxacin are not common, although absorption is greatly reduced when given with divalent and trivalent cation-containing compounds, such as antacids. Due to its potent activity against many common gram-positive and gram-negative respiratory pathogens, its proven clinical efficacy, and its favorable safety profile, gemifloxacin is a highly effective empiric treatment for community-acquired lower respiratory tract infections.

The fluoroquinolone gemifloxacin has recently been approved for the treatment of acute bacterial exacerbations of chronic bronchitis and mild community acquired pneumonia, including that caused by multidrug-resistant Streptococcus pneumoniae. Owing to the increasing prevalence of multidrug-resistant S. pneumoniae, as well as resistance to other common pathogens of acute bacterial exacerbations of chronic bronchitis and community acquired pneumonia, it is important to have new, potent antimicrobial agents for the treatment of these infections. Gemifloxacin is the most potent antimicrobial agent in vitro for S. pneumoniae, and has excellent activity against the other key pathogens of acute bacterial exacerbations of chronic bronchitis and community acquired pneumonia, including the atypical microorganisms. The clinical trial outcomes of several studies that have evaluated gemifloxacin show a range of superior clinical or bacteriologic outcomes against several current antimicrobials, including levofloxacin, clarithromycin, trovafloxacin and ceftriaxone. The safety profile of gemifloxacin is similar to that of approved agents to treat acute bacterial exacerbations of chronic bronchitis and community acquired pneumonia, with a low discontinuation rate of 2.2%. A nonphototoxic rash (usually a mild, maculopapular rash) was observed in 2.8% of patients in clinical studies.

Free gemifloxacin concentrations in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were measured by means of in vivo microdialysis to characterize the ability of gemifloxacin to penetrate human soft tissues. Twelve healthy volunteers received a single oral dose of 320 mg of gemifloxacin. The mean areas under the concentration-time curves from 0 to 10 h (AUC(0-10)) were significantly higher for soft tissue than for unbound gemifloxacin in plasma (P < 0.05). The ratios of the mean AUC(0-10) for tissue to the AUC(0-10) for free gemifloxacin in plasma were 1.7 +/- 0.7 (mean +/- standard deviation) for skeletal muscle and 2.4 +/- 1.0 for adipose tissue. The AUC(0-24) ratios for free gemifloxacin in tissues to the MIC at which 90% of frequently isolated bacteria are inhibited were close to or higher than 100 h. Therefore, based on pharmacokinetic and pharmacodynamic calculations, we conclude that gemifloxacin might be a useful therapeutic option for the treatment of soft tissue infections.

In experimental rabbit meningitis, gemifloxacin penetrated inflamed meninges well (22 to 33%) and produced excellent bactericidal activity (change in log(10) [Deltalog(10)] CFU/ml/h, -0.68 +/- 0.30 [mean and standard deviation]), even superior to that of the standard regimen of ceftriaxone plus vancomycin (-0.49 +/- 0.09 deltalog(10) CFU/ml/h), in the treatment of meningitis due to a penicillin-resistant pneumococcal strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, gemifloxacin showed good bactericidal activity (-0.48 +/- 0.16 deltalog(10) CFU/ml/h). The excellent antibacterial activity of gemifloxacin was also confirmed by time-kill assays over 8 h in vitro.

Gemifloxacin is a recently developed fluoroquinolone with potent activity against Streptococcus pneumoniae. We show that the drug is more active than moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin against S. pneumoniae strain 7785 (MICs, 0.03 to 0.06 microg/ml versus 0.25, 0.25, 1, and 1 to 2 microg/ml, respectively) and against isogenic quinolone-resistant gyrA-parC mutants (MICs, 0.5 to 1 microg/ml versus 2 to 4, 2 to 4, 16 to 32, and 64 microg/ml, respectively). Gemifloxacin was also the most potent agent against purified S. pneumoniae DNA gyrase and topoisomerase IV in both catalytic inhibition and DNA cleavage assays. The drug concentrations that inhibited DNA supercoiling or DNA decatenation by 50% (IC(50)s) were 5 to 10 and 2.5 to 5.0 microM, respectively. Ciprofloxacin and levofloxacin were some four- to eightfold less active against either enzyme; moxifloxacin and gatifloxacin showed intermediate activities. In assays of drug-mediated DNA cleavage by gyrase and topoisomerase IV, the same order of potency was seen: gemifloxacin > moxifloxacin > gatifloxacin > levofloxacin approximately ciprofloxacin. For gemifloxacin, the drug concentrations that caused 25% linearization of the input DNA by gyrase and topoisomerase IV were 2.5 and 0.1 to 0.3 microM, respectively; these values were 4-fold and 8- to 25-fold lower than those for moxifloxacin, respectively. Each drug induced DNA cleavage by gyrase at the same spectrum of sites but with different patterns of intensity. Finally, for enzymes reconstituted with quinolone-resistant GyrA S81F or ParC S79F subunits, although cleavable-complex formation was reduced by at least 8- to 16-fold for all the quinolones tested, gemifloxacin was the most effective; e.g., it was 4- to 16-fold more active than the other drugs against toposiomerase IV with the ParC S79F mutation. It appears that the greater potency of gemifloxacin against both wild-type and quinolone-resistant S. pneumoniae strains arises from enhanced stabilization of gyrase and topoisomerase IV complexes on DNA.