Objectives To evaluate the BACTEC(TM) MGIT(TM) 960/MGIT Para TB (MGIT) system for drug susceptibility testing of Mycobacterium avium subsp. paratuberculosis (MAP), a pathogen implicated in some forms of Crohn's disease. Methods MICs of 11 drugs for 10 MAP strains were determined using the MGIT system, the BACTEC(TM)460TB system (BACTEC) and conventional agar dilution methods. Results MICs determined by MGIT methods showed 80%-100% agreement (+/-1 log(2) dilution) with those determined by the BACTEC and agar dilution methods for ciprofloxacin, levofloxacin, azithromycin and clofazimine. The MGIT and BACTEC methods showed 70%, 80% and 90% agreement (+/-1 log(2) dilution) for MICs of ethambutol, rifabutin and rifampicin; agreement for all drugs increased to 100% at 2 log(2) dilution differences. For clarithromycin, the MGIT method had greater agreement with the agar dilution method (70% at the same dilution) than the BACTEC method (60% at +/-1 log(2) dilution); agreement increased to 100% at +/-2 log(2) dilutions in both cases. The MGIT and agar dilution methods agreed 60% and 100% for amikacin MICs at +/-1 log(2) dilution and +/-2 log(2) dilutions, respectively. By all methods MICs were higher than achievable serum concentrations for isoniazid and dapsone. There was 100% agreement between all three methods for azithromycin, clarithromycin and ciprofloxacin, and 80% agreement for rifampicin using published MIC thresholds available for M. avium complex strains. Conclusions This study shows that the MGIT system can be used for rapid and reliable drug susceptibility testing of MAP.

Objectives To compare the ability to select for resistance in Streptococcus pneumoniae of levofloxacin, moxifloxacin, ciprofloxacin and prulifloxacin. Methods Twenty strains of S. pneumoniae susceptible to fluoroquinolones were used. The frequencies of spontaneous single-step mutations at plasma and epithelial lining fluid (ELF) peak and trough antibiotic concentrations were calculated. Multi-step selection of resistance was evaluated by performing 10 serial subcultures on agar plates containing a linear gradient from peak to trough antimicrobial concentrations, followed by 10 subcultures on antibiotic-free agar. Resistant strains selected after multi-step selection were characterized for DNA mutations by sequencing gyrA, gyrB, parC and parE genes. Results Levofloxacin and moxifloxacin showed the lowest frequencies of mutations (median <10(-11)) at plasma peak and at ELF concentrations, while medians ranging from 10(-8) to 10(-6) were observed for ciprofloxacin and prulifloxacin. In a multi-step selection assay, ciprofloxacin and prulifloxacin selected for the highest number of resistant strains (19 and 31, respectively). No selection of resistance was observed for levofloxacin at ELF concentrations and for moxifloxacin at plasma and ELF concentrations. Mutations in parC, parE and gyrA genes were found in ciprofloxacin- and prulifloxacin-resistant strains, while only parC mutations were found for levofloxacin. Conclusions Levofloxacin and moxifloxacin are characterized by a lower propensity to select in vitro for resistance in S. pneumoniae than ciprofloxacin and prulifloxacin, when tested at plasma and lung concentrations.

Steady-state concentrations of telavancin, a novel bactericidal lipoglycopeptide, were determined in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) in 20 healthy subjects. Telavancin 10 mg/kg/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed in five subjects each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion. The telavancin plasma concentration-time profile was as reported previously. Telavancin (mean +/- standard deviation) penetrated well into ELF (3.73 +/- 1.28 microg/ml at 8 h; 0.89 +/- 1.03 microg/ml at 24 h) and extensively into AMs (19.0 +/- 16.8 microg/ml at 8 h; 45.0 +/- 22.4 microg/ml at 12 h; 42.0 +/- 31.4 microg/ml at 24 h). Mean concentrations in AMs and plasma at 12 h were 45.0 microg/ml versus 22.9 microg/ml (mean AM/plasma ratio, 1.93) and, at 24 h post-dose, 42.0 microg/ml versus 7.28 microg/ml (AM/plasma ratio, 6.67). Over the entire dosing interval, telavancin was present in ELF and AMs at concentrations up to 8-fold and 85-fold, respectively, above its MIC90 for methicillin-resistant Staphylococcus aureus (0.5 microg/ml). Pulmonary surfactant did not affect telavancin's in vitro antibacterial activity. Telavancin was well tolerated. These results support further clinical evaluation of telavancin for treating gram-positive respiratory infections.

OBJECTIVE: A double-blind, noninferiority trial was conducted to establish the safety and efficacy of a once-daily, 5-day course of levofloxacin 750 mg compared to a twice-daily, 10-day course of ciprofloxacin in complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). This report focuses on subjects with AP.Research design and methods: Adult male and female subjects with clinical signs and symptoms of AP and laboratory confirmation of their diagnosis were randomized to receive one dose of levofloxacin 750 mg once daily intravenously (IV) or orally and one dose of placebo for 5 days, followed by placebo; or ciprofloxacin 400 mg IV and/or 500 mg orally twice daily for 10 days.MAIN OUTCOME MEASURES: The primary, prospectively defined end point was microbiologic eradication at post-therapy (study days 1522). Secondary outcomes included clinical response and safety and tolerability.RESULTS: In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference 3.4, 95% CI 14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference 0.9, 95% CI 7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6%(mITT) and in 92.5% vs. 89.5%(ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin.CONCLUSIONS: High-dose, short-course therapy with levofloxacin in subjects with AP is at least as effective as standard 10-day therapy with ciprofloxacin.

The present work was aimed to compare levofloxacin pulmonary disposition after systemic or inhalatory delivery and to evaluate the influence of respiratory pattern on lung distribution. An experimental model of the isolated lung of the rat was used. Twenty-four Wistar rats were distributed in four groups receiving levofloxacin under different experimental conditions including systemic or pulmonary delivery and higher or lower respiratory frequency with lower or higher tidal volume, respectively. Levofloxacin (500mug) was administered as a bolus injection or by inhalation. Lung tissue samples as well as efferent and broncoalveolar fluid were collected. Quantification of levofloxacin levels in all samples was performed by a high-performance liquid chromatography (HPLC) technique. Pulmonary distribution coefficient of levofloxacin after systemic delivery showed mean values of 1.19+/-0.13 and 3.34+/-0.61ml/g for each respiratory pattern assayed. The partition coefficients estimated from simultaneous drug level in lung tissue and efferent fluid (EF) are in agreement with the above values. Comparison of systemic and pulmonary administration reveals statistical significant differences between partition coefficients showing much higher values for the latter route (8.01+/-5.53 versus 2.86+/-1.35). In conclusion, inhalation compared to systemic administration improves levofloxacin access to the lung tissue; the experimental approach used here to assess the pulmonary drug disposition may be a useful model for biopharmaceutical studies of inhaled therapeutics.

In spite of development and wide use of antibiotics, pneumonia is still the leading cause of infection related mortality worldwide (1), and antibiotic resistance has become more frequent in the major pathogens of pneumonia during the past several decades. In order to defeat and prevent antibiotic resistance, antibiotics need to be used based on pharmacokinetics (PK) and pharmacodynamics (PD)(7, 11, 36)....

This study investigated whether treating acute exacerbations of COPD (AE-COPD) with levofloxacin modifies the long-term outcome of COPD patients in comparison with standard antibiotic regimens. Methods: A 6-month open-label clinical trial of AE-COPD patients compared the outcomes of treating with levofloxacin versus standard therapy (clarithromycin, cefuroxime, or amoxicillin/clavulanate) at recommended doses for 10 days. Several variables were analysed: pulse oximetry, FEV(1), health-related quality of life, infection-free interval, number of exacerbations, hospitalizations due to an exacerbation and mortality. Results: Of the 116 patients initially enrolled, completion or withdrawal information was available for 50 patients in the levofloxacin arm and 52 in the standard therapy arm. At the end of the study, there were no differences in mortality (17.8% vs. 22.9%, P = 0.53), number of exacerbations (33 vs. 41, P = 0.40), pulse oximetry (median 91.71% vs. 92.46%, P = 0.18), FEV(1)(median 51.31% vs. 47.14%, P = 0.30), health-related quality of life (median 8.63 vs. 10.75, P = 0.94) and infection-free interval (median 112 vs. 101 days, P = 0.72), for the levofloxacin and standard therapy, respectively. However, 12 out of 33 (33.6%) exacerbations treated with levofloxacin required in-hospital management versus 27 out of 41 (65.8%) treated with standard therapy (P = 0.02). Conclusion: This preliminary study suggests that 10-day treatment of AE-COPD with levofloxacin is associated with a reduction in hospitalizations compared with standard antibiotics despite there being no significant benefit in other outcome variables.

Critically ill patients are on the increase in the present clinical setting. Aging of our population and increasingly aggressive medical and therapeutic interventions, including implanted foreign bodies, organ transplantation and advances in the chemotherapy of malignant diseases, have created a cohort of particularly vulnerable patients. Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. This organism is frequently feared because it causes severe hospital-acquired infections, especially in immunocompromised hosts, and is often antibiotic resistant, complicating the choice of therapy. The epidemiology, microbiology, mechanisms of resistance and currently available and future treatment options for the most relevant infections caused by P. aeruginosa are reviewed.

Two of the most serious respiratory tract infections are community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB). The most common pathogens found in patients with these infections are Haemophilus influenzae and Streptococcus pneumoniae. Pseudomonas aeruginosa is also relatively common, particularly in elderly patients with AECB. S. pneumoniae and P. aeruginosa are also of concern in relation to the development of resistance to antimicrobial drugs. The administration of antibiotics at doses that result in concentrations exceeding the mutant prevention concentration at the site of infection is one strategy to prevent the development of drug-resistant pathogens. AECB is associated with a high risk of in-hospital mortality, particularly in patients treated in the intensive care unit. CAP is also associated with significant risks and often requires treatment under hospital supervision. Several patient-related factors help identify those patients who are most at risk of mortality and morbidity. Treatment should be tailored towards the severity of the disease. The fluoroquinolones, such as levofloxacin, are an effective treatment option for AECB and CAP. Compared with many other antibiotics, resistance to levofloxacin remains low for most infecting pathogens. The oral bioavailability of levofloxacin is over 99%, enabling simple switching from intravenous to oral therapy during treatment. It is also preferentially distributed to compartments in the lung, thus achieving high concentrations at the site of respiratory tract infections. Combined with cover of the major infecting pathogens found in patients with AECB and CAP, and a cost-effective treatment compared with many alternative therapies, levofloxacin is an attractive option for the treatment of at-risk patients with these respiratory tract infections.

BACKGROUND: The efficacy and safety of 750-mg, 5-day levofloxacin was recently shown to be comparable to 500-mg, 10-day levofloxacin in a randomized, double-blind, multicentre clinical trial for mild-to-severe community-acquired pneumonia (CAP). This subgroup analysis attempted to compare the safety and efficacy of a short-course levofloxacin regimen with traditional levofloxacin dosing for PSI Class III/IV patients. METHODS: This retrospective, subgroup analysis focused on Pneumonia Severity Index Class III and IV patients enrolled in the study. Measurements included clinical and microbiological success rates, adverse events, and symptom resolution by day 3 of therapy. RESULTS: Of the 528 patients in the ITT population, 219 (41.5%) were categorized as PSI Class III/IV and included in this analysis. Among the clinically evaluable patients, 90.8%(69/76) of patients treated with the 750-mg regimen achieved clinical success, compared with 85.5%(71/83) treated with 500-mg levofloxacin (95% CI,-15.9 to 5.4). Eradication rates in the microbiologically evaluable population were comparable for the 750- and 500-mg regimens (88.9% vs 87.5%, respectively; 95% CI,-18.3 to 15.6). Both regimens were well tolerated and had comparable safety profiles. A greater proportion of patients in the 750-mg treatment group experienced resolution of fever (48.4% vs 34.0%; P=.046) and purulent sputum (48.4% vs 27.5%; P=.007) by day 3 of therapy. CONCLUSIONS: The 750-mg, 5-day levofloxacin course achieved comparable clinical and microbiologic efficacy to the 500-mg, 10-day regimen. By day 3 of therapy, a greater proportion of patients in the 750-mg group had objective and subjective resolution of fever. Further research is needed to determine the economic significance of short-course levofloxacin therapy.

Respiratory infections caused by Pseudomonas aeruginosa present significant treatment challenges, including that of overcoming intrinsic and adaptive resistance by these organisms. The fluoroquinolones may provide an effective option for treating these infections. In this analysis, we report on the efficacy of levofloxacin in the treatment of community-acquired pneumonia (CAP) and nosocomial pneumonia caused by P. aeruginosa using information from nine clinical studies supported by Johnson & Johnson Pharmaceutical Research and Development (Raritan, NJ) or Ortho-McNeil Pharmaceutical (Raritan, NJ). From these studies, a total of 36 patients were identified with pneumonia caused by P. aeruginosa and treated with levofloxacin (750 mg or 500 mg). For patients diagnosed with nosocomial pneumonia, levofloxacin treatment achieved a 64.7%(11/17) clinical success rate, compared with 41.2%(7/17) with comparator treatment (imipenem/cilastatin followed by ciprofloxacin) in the microbiologically evaluable population. Eradication rates were 58.8% with levofloxacin treatment vs. 29.4% with comparator (95% CI,-64.2 to 5.4). For levofloxacin-treated CAP patients with P. aeruginosa infections (n = 19), clinical success and microbiological eradication rates in the microbiologically evaluable population were 89.5% and 78.9%, respectively. Several limitations of this analysis exist including that this was a retrospective evaluation that pooled data from multiple studies with varying protocols, the number of patients included was limited, and the nosocomial pneumonia patients used adjunctive therapy with an antipseudomonal beta-lactam in most cases. Nonetheless, these findings suggest that levofloxacin may play a role in the treatment of these difficult respiratory infections.

The use of levofloxacin in critically ill patients has progressively increased since commercial marketing of the drug in 1999, despite the fact that few studies have been designed to assess the use of levofloxacin in this population. Pharmacological characteristics, broad spectrum of activity, and tolerability account for the high interest in the drug for the treatment of different infectious diseases, including ventilator-associated pneumonia (VAP), and the recommendation of levofloxacin in guidelines developed by a number of scientific societies. According to pharmacokinetic-pharmacodynamic data, it seems reasonable to assume that an increase in activity follows from a larger dose, so that 500 mg/12 h is adequate in patients with VAP. In critically ill patients with VAP, levofloxacin monotherapy is indicated for empirical treatment of patients with early onset pneumonia without risk factors for multiresistant pathogens, and in combination therapy for late onset VAP or for patients at risk for multiresistant pathogens. The use of levofloxacin in combination therapy is supported by multiple reasons, including: increased empirical coverage in infections with suspected intracellular pathogens; substitution for more toxic antimicrobial agents (e.g., aminoglycosides) in patients with renal dysfunction and in those at risk for renal insufficiency; and severity of systemic response to infection (septic shock) that justifies multiple treatment with better tolerated antibiotics. The availability of the oral formulation allows sequential therapy, switching from the intravenous route to the oral route. Levofloxacin is well tolerated by critically ill patients, with few adverse events of mild to moderate severity.

The pathological changes in chronic bronchitis (CB) produce airflow obstruction, reduce the effectiveness of the mucocilliary drainage system and lead to bacterial colonisation of bronchial secretion. The presence of bacteria induces an inflammatory response mediated by leukocytes. There is a direct relationship between the degree of impairment of the mucocilliary drainage system, the density of bacteria in mucus and the number of leukocytes in the sputum. Purulent sputum is a good marker of a high bacterial load. Eventually, if the number of leukocytes is high, their normal activity could decrease the effectiveness of the drainage system, increase the bronchial obstruction and probably damage the lung parenchyma. Whenever the density of bacteria in the bronchial lumen is >/= 10(6) CFU/mL, there is a high probability that the degree of inflammatory response will lead to a vicious cycle which in turn tends to sustain the process. This situation can arise during the clinical course of any acute exacerbation of CB, independently of its aetiology, provided the episode is sufficiently severe and/or prolonged. Fluoroquinolones of the third and fourth generation are bactericidal against most microorganisms usually related to acute exacerbations of CB. Their diffusion to bronchial mucus is adequate. When used in short (5-day) treatment they reduce the bacterial load in a higher proportion than is achieved by beta-lactam or macrolide antibiotics given orally. Although the clinical cure rate is similar to that obtained with other antibiotics, the time between exacerbations could be increased.

STUDY OBJECTIVES: Levofloxacin is a fluoroquinolone antimicrobial agent for which pharmacodynamic relationships between the maximum serum antibiotic concentration (Cmax)/minimum inhibitory concentration (MIC) ratio and/or the area under the serum concentration-time curve during a 24-h dosing period (AUC(0-24))/MIC ratio and clinical and/or microbiological outcomes have been developed. In this study we examined the relationship between the in vitro bacterial susceptibility to levofloxacin, the achieved levofloxacin serum and sputum concentrations, and the in vivo bacterial eradication in patients with acute exacerbations of chronic bronchitis. PATIENTS AND INTERVENTIONS: Thirty patients received levofloxacin, 500 mg/d po for 7 days. Samples of venous blood and sputum for the determination of levofloxacin concentrations were collected on day 1 immediately prior to dosing, and then at 1, 4, 8, 12, and 24 h. RESULTS: The mean peak concentration in serum (6.5 mg/L) was found 1 h after administration, and at 4 h after administration in sputum (5.1 mg/L). Levofloxacin was always detectable 24 h after administration from both samples. Successful treatment occurred in 90%(27 of 30 patients) when assessed both clinically and bacteriologically. Treatment was successful in eight patients when the AUC(0-24)/MIC ratio was > 40 for serum, and in nine patients when it was > 30 for sputum. Treatment was also successful in seven patients when the Cmax/MIC ratio was > 5.01 for serum, and in nine patients when the Cmax/MIC ratio was > 4.01 for sputum. Treatment was successful in 90%(27 of 30 patients) when the AUC(0-24)/MIC ratio was > 125 for serum and > 100 for sputum, and when Cmax/MIC was > 10.01 for serum and > 8.01 for sputum following the first dose. CONCLUSIONS: The pharmacodynamics values that we have obtained in sputum with levofloxacin may be used as predictors of therapy outcomes.

Acute exacerbations of chronic bronchitis (AECB), which are characteristic of chronic obstructive pulmonary disease (COPD), contribute to morbidity and decreased quality of life for patients with COPD. A significant proportion of these exacerbations are due to bacterial infections. The Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria provide guidance for choosing the optimal drug at its optimal dose and duration for antimicrobial treatment of AECB due to bacterial infection. Evidence-based guidelines recommend stratifying patients according to risk factors to improve selection of targeted antimicrobial therapy. With increasing rates of resistance to some antimicrobials, resistance is also an important consideration for reducing treatment failures and decreasing the need for further pharmacologic treatment. Fluoroquinolones are recommended as first-line therapy for patients with chronic bronchitis who have risk factors; gatifloxacin, gemifloxacin, and levofloxacin are highly active against commonly encountered pathogens. Safety profiles are an important consideration because adverse events and poor tolerability can reduce patient adherence rates, which in turn can lead to poorer outcomes. Safety profiles also become an important consideration as shorter-course, higher-dose therapies become more prevalent. First-line therapy with a well-tolerated antibiotic that is active against the predominant pathogens, combined with low resistance rates and a convenient once-a-day dosing regimen, may reduce overall costs. Fluoroquinolones exhibit low resistance, good activity levels, and high respiratory penetration, and they are particularly well suited for shorter-course, higher-dose regimens in selected patients. Shorter-course, higher dose regimens, in turn, may be more effective, cost-efficient, and appropriate for controlling the rise of resistance than standard regimens.

Respiratory tract infections (RTIs) that may require hospitalization include acute exacerbations of chronic bronchitis (AECB), community-acquired pneumonia (CAP), and hospital-acquired pneumonia (HAP), which includes ventilator-associated pneumonia (VAP). Healthcare-associated pneumonia (HCAP) is treated similar to HAP and may be considered with HAP. For CAP requiring hospitalization, the current guidelines for the treatments of RTIs generally recommend either a beta-lactam and macrolide combination or a fluoroquinolone. The respiratory fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin) are excellent antibiotics due to high levels of susceptibility among gram-negative, gram-positive, and atypical pathogens. The fluoroquinolones are active against > 98% of Streptococcus pneumoniae, including penicillin-resistant strains. Fluoroquinolones are also recommended for AECB requiring hospitalization. Evidence from clinical trials suggests that levofloxacin monotherapy is as efficacious as combination ceftriaxone-erythromycin therapy in the treatment of patients hospitalized with CAP. For early-onset HAP, VAP, and HCAP without the risk of multidrug resistance, ceftriaxone, ampicillin-sulbactam, ertapenem, or one of the fluoroquinolones is recommended. High-dose, short-course therapy regimens may offer improved treatment due to higher drug concentrations, more rapid killing, increased adherence, and the potential to reduce development of resistance. Recent studies have shown that short-course therapy with levofloxacin, azithromycin, or telithromycin in patients with CAP was effective, safe, and tolerable and may control the rate of resistance.

The increasing resistance of Streptococcus pneumoniae, the most important community respiratory pathogen, to beta-lactams and other first-line antimicrobial agents usually employed for the empirical treatment of lower respiratory tract infections has led to the inclusion, in several current guidelines, of a fluoroquinolone with improved activity against pneumococci as the first choice agent for the management of such infections. The excellent microbiological, pharmacokinetic, and pharmacodynamic characteristics of the new fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin, and gatifloxacin) have encouraged their growing use, probably contributing to the emergence of fluoroquinolone-resistant pneumococci; although pneumococcal resistance to new fluoroquinolones is currently low, there is still concern about the potential for widespread emergence of resistance to these agents if they become indiscriminately used. Levofloxacin clinical failures have already been reported in the management of patients with pneumococcal community-acquired pneumonia; development of resistance in clinical isolates of S. pneumoniae has prompted a critical reexamination of the newer fluoroquinolones to assess their potency and to preserve their activity. An understanding of the pharmacokinetic and pharmacodynamic properties, allowing selection of the most potent fluoroquinolone, will reduce the opportunity for resistance to develop. Finally, a targeted use of these agents will maintain class efficacy.

The study of pharmacodynamics has greatly enhanced our understanding of antimicrobials and has enabled us to optimize dosing regimens. Applying this knowledge to the clinical setting can be critical for the treatment of Pseudomonas aeruginosa infections. Because of its selectively permeable outer membrane and multiple efflux pump mechanisms, P. aeruginosa has high intrinsic resistance to many available antimicrobials. Numerous studies have established pharmacodynamic values for concentration-dependent agents (maximum serum concentration : minimum inhibitory concentration [MIC] and area under the serum concentration-time curve : MIC) and concentration-independent agents (i.e., percentage of time that the drug concentration remains greater than the MIC) that help predict the probability of a successful outcome. Current therapies attempt to meet these target values. However, to reduce the risk of clinical failures, combination therapy (typically, a beta -lactam with an aminoglycoside or fluoroquinolone) is commonly used to enhance eradication rates and decrease the risk of developing resistance. Although combination therapy ensures a greater chance of selection of appropriate treatment, timely initial administration of antimicrobial therapy remains a key factor for reducing the likelihood of death for these patients.