Dose Of Levofloxacin Research Articles

Comparative Pharmacokinetics of Levofloxacin in Healthy and Renal Damaged Muscovy Ducks following Intravenous and Oral Administration

The pharmacokinetics aspects of levofloxacin were studied in healthy and experimentally renal damaged Muscovy ducks after single intravenous (IV) and oral (PO) dose of 10 mg kg−1 bwt. Following IV administration, elimination half-life (t 1/2(β)) and mean residence time (MRT) were longer in renal damaged ducks than in healthy ones. Total clearance (Cltot) in renal damaged ducks (0.20 L kg−1 h−1) was significantly lower as compared to that in healthy ones (0.41 L kg−1 h−1). Following PO administration, the peak serum concentration (C max) was higher in renal damaged than in healthy ducks and was achieved at maximum time (t max) of 2.47 and 2.05 h, respectively. The drug was eliminated (t 1/2(el)) at a significant slower rate (3.94 h) in renal damaged than in healthy ducks (2.89 h). The pharmacokinetic profile of levofloxacin is altered in renal damaged ducks due to the increased serum levofloxacin concentrations compared with that in clinically healthy ducks. Oral administration of levofloxacin at 10 mg kg−1 bwt may be highly efficacious against susceptible bacteria in ducks. Also, the dose of levofloxacin should be reduced in renal damaged ducks. Pharmacokinetic/pharmacodynamic integration revealed significantly higher values for C max/MIC and AUC/MIC ratios in renal damaged ducks than in healthy ones, indicating the excellent pharmacokinetic characteristics of levofloxacin in renal damaged ducks.

Occurrence of infection following prostate biopsy procedures in Japan

We retrospectively investigated the incidence of genitourinary tract infection in 5895 patients who underwent transrectal and/or transperineal prostate biopsy procedure between January and December 2011 at 46 institutions belonging to Japanese Research Group for Urinary Tract Infection (JRGU). The total rate of genitourinary tract infection after prostate biopsy was 0.76%, while that following transrectal procedure was 0.83% and following transperineal procedure was 0.57%, which were not significantly different. In contrast, febrile infection associated with a fever (≥38°C) occurred significantly more frequently after transrectal (0.71%) than transperineal (0.16%) approach (P=0.04). Notably, in infectious cases, Escherichia coli was most frequently isolated. Of the 9 E.coli strains isolated by urine culture, 6 (66.7%) produced extended spectrum β-lactamase (ESBL) and 7 (77.8%) showed levofloxacin resistance. Similarly, of 6 E.coli strains isolated by blood culture, 4 (66.7%) produced ESBL and 6 (100%) showed levofloxacin resistance. When the efficacy of antimicrobial prophylaxis (AMP) with levofloxacin for the patients undergoing transrectal or transperineal biopsy was compared between a single dose (500mg) and that given for 2 or more days, no significant difference was observed for the rate of infection (transrectal: 0.82% vs. 1.04%, p=0.94; transperineal: 0.30% vs. 0.46%, p=0.68). Although a single dose of levofloxacin for AMP is sufficient to prevent genitourinary infection after transrectal or transperineal prostate biopsy, and recommended in this era of increased multi-drug resistant pathogens, the increase in fluoroquinolone-resistant E.coli and ESBL-producing E.coli has emerged as a profound problem for surveillance.

Characterization of fluoride-tolerant halophilic Bacillus flexus NM25 (HQ875778) isolated from fluoride-affected soil in Birbhum District, West Bengal, India

A new Gram-positive, nonpigmented, rod-shaped fluoride-tolerant bacterial strain, NM25, was isolated from waterlogged muddy field soil collected from the fluoride endemic area of Rampurhat II block (average fluoride in water, 4.7 mg/l, and in soil, 1.5 mg/kg) in Birbhum District, West Bengal, India. The study was undertaken to characterize the fluoride-tolerant bacterial isolate, to determine its role in bioaccumulation of fluoride, and to analyze the water and soil quality of the bacterial environment. The isolate was positive for catalase, lipase, urease, protease, oxidase, and H2S production, but negative for indole production, nitrate reduction, and Vogues-Proskauer test. The organisms were sensitive to recommended doses of ofloxacin, kanamycin, rifampicin, levofloxacin, vancomycin, gatifloxacin, gentamicin, doxycycline, streptomycin, and nalidixic acid but resistant to ampicillin. Based on the phenotypic characteristics, 16S rRNA gene sequence, and phylogenetic analysis, the bacterial isolate NM25 was identified as Bacillus flexus. The G+C content of the 16S rDNA was 53.14 mol%. This strain tolerated up to 20% (w/v) NaCl in nutrient agar medium and was grown at the pH range 4-12. It reduced fluoride concentration up to 67.45% and tolerated more than 1,500 ppm of fluoride in brain-heart infusion agar medium.

Testing the mutant selection window hypothesis with Escherichia coli exposed to levofloxacin in a rabbit tissue cage infection model

The purpose of this study was to test the mutant selection window (MSW) hypothesis with Escherichia coli exposed to levofloxacin in a rabbit model and to compare in vivo and in vitro exposure thresholds that restrict the selection of fluoroquinolone-resistant mutants. Local infection with E. coli was established in rabbits, and the infected animals were treated orally with various doses of levofloxacin once a day for five consecutive days. Changes in levofloxacin concentration and levofloxacin susceptibility were monitored at the site of infection. The MICs of E. coli increased when levofloxacin concentrations at the site of infection fluctuated between the lower and upper boundaries of the MSW, defined in vitro as the minimum inhibitory concentration (MIC99) and the mutant prevention concentration (MPC), respectively. The pharmacodynamic thresholds at which resistant mutants are not selected in vivo was estimated as AUC24/MPC > 20 h or AUC24/MIC > 60 h, where AUC24 is the area under the drug concentration time curve in a 24-h interval. Our finding demonstrated that the MSW existed in vivo. The AUC24/MPC ratio that prevented resistant mutants from being selected estimated in vivo is consistent with that observed in vitro, indicating it might be a reliable index for guiding the optimization of antimicrobial treatment regimens for suppression of the selection of antimicrobial resistance.

Pharmacokinetics of sunitinib in combination with fluoroquinolones in rabbit model

BackgroundFluoroquinolones are widely prescribed antibiotics. Ciprofloxacin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for levofloxacin and moxifloxacin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib which is indicated for the treatment of gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC). This study investigated the effects of single intravenous dose of ciprofloxacin, levofloxacin or moxifloxacin on the pharmacokinetics of sunitinib. MethodsRabbits were subjected to one of four study drug groups: sunitinib + ciprofloxacin (n=6), sunitinib + levofloxacin (n=6), sunitinib + moxifloxacin (n=6), or sunitinib alone (n=6). The rabbits were treated with sunitinib in the oral dose of 25mg. The antibiotics were administered intravenously at the doses of 20, 25 and 20mg/kg, respectively. Plasma concentrations of sunitinib and active metabolite (SU12662) were measured with validated HPLC method with UV detection. ResultsThe comparison of sunitinib Cmax for the sunitinib + ciprofloxacin, sunitinib + levofloxacin, sunitinib + moxifloxacin group and that for the sunitinib group gave ratios of 1.81 (90% CI 1.33, 2.44), 1.59 (90% CI 1.18, 2.16), 1.06 (90% CI 0.79, 1.44), respectively. The comparison of sunitinib AUC0-∞ for the sunitinib + ciprofloxacin, sunitinib + levofloxacin, sunitinib + moxifloxacin group and that for the sunitinib group gave ratios of 2.90 (90% CI 1.32, 6.37), 2.45 (1.11, 5.39), 1.58 (0.70, 1.56), respectively. The mean sunitinib tmax was similar for all four groups. The mean Cmax for SU12662 was similar for both the sunitinib + moxifloxacin and sunitinib groups (p=0.9593). However, the mean Cmax for SU12662 for the groups: sunitinib + ciprofloxacin and sunitinib + levofloxacin were higher (p=0.0045 and 0.0672, respectively). ConclusionsThe study proved a significant effect of the coadministration of ciprofloxacin and levofloxacin on the pharmacokinetics of sunitinib in rabbits. The influence of moxifloxacin on the pharmacokinetics of sunitinib was insignificant. Therefore, this fluoroquinolone seems to be the most appropriate in combination with this tyrosine kinase inhibitor.

A case report from Nepalese community pharmacy on levofloxacin induced severe abdominal pain

A 46-year-old female patient developed severe abdominal pain shortly after taking levofloxacin, 1000mg for acute bacterial sinusitis. The pain started after taking the first dose of levofloxacin and became worse after the second dose. The patient was unable to do daily physical activities. The pain resolved upon discontinuation of levofloxacin and symptomatic therapy. Other factors that may cause abdominal pain were ruled out. This case is of interest as it documents severe abdominal pain due to levofloxacin requiring discontinuation of therapy and describes its appropriate management. In addition, it highlights the vital role that community pharmacists could play in managing adverse drug reactions (ADRs) and preventing potential Drug Related Problems (DRPs).

Comparative antibacterial effects of moxifloxacin and levofloxacin on Streptococcus pneumoniae strains with defined mechanisms of resistance: impact of bacterial inoculum

We aim to further define the impact of the mechanism of fluoroquinolone resistance and inoculum load on the pharmacodynamic effects of levofloxacin and moxifloxacin on Streptococcus pneumoniae. The antibacterial effects of and emergence of resistance (EoR) to moxifloxacin (400 mg once daily) or levofloxacin (750 mg once daily or 500 mg twice daily) were compared using five S. pneumoniae strains containing no known resistance mechanisms, efflux resistance mechanisms, a parC mutation or parC and gyrA mutations, at high (10(8) cfu/mL) and low (10(6) cfu/mL) inocula. An in vitro pharmacokinetic model was used and simulations were performed over 96 h. After drug exposure, isolates were tested for the presence of efflux pumps and mutations in the quinolone resistance-determining regions. A high inoculum diminished the antibacterial effect of moxifloxacin and levofloxacin. Levofloxacin at both dosages produced EoR with all strains. Levofloxacin regimens with AUC/MIC ratios <100 produced EoR. Moxifloxacin produced EoR with the parC strain only. Levofloxacin dosing regimens with low AUC/MIC ratios select for efflux pump overexpression, leading to fluoroquinolone resistance. Levofloxacin dosing may select for gyrA mutations, inducing moxifloxacin resistance. These data confirm that a fluoroquinolone AUC/MIC ratio of >100 is required for prevention of EoR.

Comparative efficacy of levofloxacin and ceftriaxone in the treatment of community acquired pneumonia in children

Pneumonia is a common cause of mortality and morbidity in under-5 children throughout the world. Globally an estimated 156 million new episodes of pneumonia occur each year in children and 2 million children die from pneumonia each year which is 20 percent of all deaths of children under five years old. Ceftriaxone is a commonly used drug for empiric treatment of community acquired pneumonia (CAP) in children. Levofloxacin may be an adequate option for empiric therapy in treatment of CAP in children because it gives the broad spectrum activity against both bacterial and atypical pathogens causing CAP and studies suggest that it can be safely used in children. This open labeled, randomized, comparative clinical trial was carried out in the Department of Pediatrics, Sylhet MAG Osmani Medical College Hospital, Bangladesh during January, 2011 & December, 2012 to compare the efficacy of levofloxacin and ceftriaxone in the treatment CAP in children. A total 70 cases of CAP were enrolled. 35 cases were allocated to levofloxacin group and another 35 cases to ceftriaxone group. At first the study cases were selected by systematic random sampling. Group allocation to either levofloxacin or ceftriaxone group was done by lottery method. Total duration for receiving study drugs was seven days. Dose of levofloxacin was 10 mg/kg/day children ≥5 years, where as it was 10 mg/kg 12 hourly in 6 months to Clinical responses were categorized as cured and treatment failure. 91.43% cases were cured in levofloxacin group, whereas cure rate of ceftriaxone group was 68.57% which was statistically significant (p = 0.0168). Adverse effects of levofloxacin were found as skin rash in 1 case and vomiting in 2 cases whereas skin rash was found in 1 case in ceftriaxone group. So it can be concluded that levofloxacin is more effective than ceftriaxone in the treatment of CAP in children.

Four consecutive cases of Achilles tendon disorders associated with levofloxacin treatment in hemodialysis patients

To the Editor Quinolone-induced tendon injury is an uncommon complication with an estimated rate of only 0.14–0.4 % in an otherwise healthy population [1]. However, an epidemiologic study clearly showed that current exposure to quinolone increased the risk of Achilles tendon rupture (adjusted odds ratio 4.3) [2]. Although the mechanism by which quinolones are thought to cause tendon injury has not been established, a number of suggestions, including an ischemic vascular process, direct toxicity to the collagen, oxidative damage, and the structure activity of the quinolone molecule, have been made [1]. Moreover, there is an accumulation of case reports related to quinolone use in patients with renal impairment, including a case described in Clinical and Experimental Nephrology [3]. Renal transplantation, advanced age, renal failure and/or hemodialysis (HD), hyperparathyroidism, rheumatic diseases, gout, and use of corticosteroids have been proposed as predisposing factors [1]. It is of particular interest to nephrologists that patients with end-stage renal diseases are prone to these conditions. We herein report four cases of Achilles tendon disorders following levofloxacin administration in HD patients that occurred in a 2-year period from May 2009 to May 2011 at our hospital. The clinical characteristics of the patients are summarized in Table 1. On careful examinations by an orthopedist, rupture was not evident in any of cases. In consideration of the following clinical courses, bilateral tendonitis was the most likely disorder. All were undergoing thrice-weekly HD and received oral levofloxacin administration: patient 1 at a daily dose of 200 mg (twice a day) and the other three patients at 500 mg on the first day and then 250 mg every 48 h according to the revised dose for patients with severe renal impairment. In Japan, the regimen for levofloxacin was revised in 2009 in this manner, with the intention of enhancing efficacy and avoiding bacterial resistance based on pharmacokinetics and pharmacodynamics [4]. Thus, it is intriguing that we experienced four consecutive cases of Achilles tendon disorders in patients taking a relatively high dose of levofloxacin in this transition period. These observations implicate dose dependency and reduced drug clearance in the development of the tendon disorder, in support of previous reports [1, 2]. Incidentally, levofloxacin was prescribed simply because of the availability at our facility. In fact, other quinolones such as pefloxacin, ciprofloxacin, and norfloxacin accounted for the greater proportions of quinolone-associated tendinopathy in a literature review [1]. Second, the manifestations emerged shortly after administration, within a couple of days in most cases, and completely disappeared 2–4 months later without requiring hospitalization or surgery. Consistent with our experience, Khaliq et al. [1] documented that 50 % of tendonitis cases occurred within 6 days after initiation of fluoroquinolone therapy, during the time when the antimicrobial therapy might still be in effect. Interventions included discontinuation of the drug in the majority of cases [1]. Similarly, levofloxacin was presumptively discontinued in three of our patients, and in patient 1 medication had already ceased at the time of onset because of resolution of the infectious disease. Magnetic resonance imaging was performed only in the latest case (patient 4) with reference to an Images in S. Takeda T. Imai Y. Chaki Dialysis Center, Oyama Municipal Hospital, 1-15 Wakagi-cho, Oyama, Tochigi, Japan

Severe shoulder tendinopathy associated with levofloxacin

Fluoroquinolone (FQ)-associated tendinopathy and myopathy are uncommon but well recognized complications of the use of this class of antibacterial agents. The case of a 63-year-old previously asymptomatic female patient who developed severe left shoulder tendinopathy after surreptitiously doubling the prescribed dose of levofloxacin for the treatment of community-acquired pneumonia is reported here. Surgical stabilization with suture anchors and subacromial decompression were needed.

Levofloxacin-Induced Tendinopathy of the Hip

To describe what we believe to be the first reported possible case of tendinopathy of the hip in a patient receiving levofloxacin. A 58-year-old male with recurrent otitis media was admitted for left lateral hip pain of 10 on a scale of 10. He had started a 5-day course of levofloxacin 750 mg/day 10 days before he began experiencing pain. He also took simvastatin 20 mg/day and walked 90 minutes each day. He was treated with oxycodone with acetaminophen and physical therapy. His pain had improved significantly at a 10-day recheck. Fluoroquinolone-induced tendinopathy has been well-reported in the literature, but most cases involve pefloxacin and affect the Achilles tendon. Only 11 cases of tendinopathy have been reported with levofloxacin based on a MEDLINE search (1966-December 2011). This is the first known case reported that involved tendinopathy of the hip believed to be caused by fluoroquinolones. The Naranjo probability scale revealed a possible adverse reaction of levofloxacin-induced tendinopathy of the hip. Contributing factors likely included the high dose of levofloxacin, concomitant use of a statin, and strenuous physical activity. Health care professionals should be aware of the possibility of tendinopathy of the hip in patients who receive fluoroquinolones. Thorough history for possible risk factors should be obtained. Patients on fluoroquinolones at risk for tendinopathy should be counseled to avoid strenuous physical activity.

Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects

There is no consensus as to what extent the results of thorough QT interval/corrected QT interval (QT/QTc) studies need to be bridged. The results of two studies using levofloxacin in Japanese and Caucasian subjects were compared in a post hoc analysis to investigate the similarity of dose–effect responses. Concentration–response analysis based on the change of QT interval corrected using Fridericia's formula (QTcF) from time-matched placebo was planned and performed in the combined data sets. At the geometric maximum mean concentration for the two doses in the Caucasian study, a predicted effect on QTcF comparable to the effects observed was found. For the Japanese study, the predicted effect was lower, but the difference was not statistically significant. No statistically significant differences in QTc-prolonging effect between Japanese and Caucasian subjects were observed following levofloxacin dosing. However, a trend suggests that Caucasian subjects may be more sensitive. Age and sex did not have an impact.

Assessment of Helicobacter pylori eradication rate of triple combination therapy containing levofloxacin

Owing to its high efficacy, ease of use, perfect adaptation and low complication profile, it is suggested that the triple therapy combination consisting of levofloxacin, amoxicillin and proton pump inhibitor may be an alternative for the first-line and second-line treatment of Helicobacter pylori. The aim of this study is to evaluate the efficacy of the triple therapy regimen containing two different doses of levofloxacin in the first-line eradication treatment. 110 naïve patients with anti Helicobacter pylori treatment indications according to Maastricht III Consensus Report were included to the study. Patients were randomized into two groups as the patients treated with a levofloxacin (500 mg o.i.d), amoxicillin (1 g b.i.d) and proton pump inhibitor (b.i.d) combination for 10 days (Group 1, n=60) and patients treated with a levofloxacin (500 mg b.i.d), amoxicillin (1 g b.i.d) and proton pump inhibitor (b.i.d) combination for 10 days (Group 2, n=50). Eradication rate was assessed at the 6th week of therapy just subsequent to termination of treatment. 110 treatment-naïve patients (60 female, mean age: 44.1±14.7 years) were randomized and all patients completed the study. Helicobacter pylori eradication of the Group 1 was 60% and in Group 2 was 72.7%. The difference between the two groups was not statistically significant (p=0.427). None of patients experienced severe complication that would lead to discontinuation of therapy. It is observed that the efficacy of the triple therapy combination containing levofloxacin is not within acceptable limits for the first-line Helicobacter pylori eradication.

Effect of levofloxacin on lithium – a pharmacokinetic study in rabbits

The aim of this study was to evaluate potential drug-drug interaction between lithium and levofloxacin. The study was conducted on New Zealand white rabbits with three groups having two subgroups each (n = 12). The first group compared the pharmacokinetic (Pk) parameters of lithium when lithium was given as a single dose (56 mg/kg) and when lithium was co-administered with levofloxacin (35 mg/kg). The second group compared the Pk parameters of lithium when lithium was given for 6 days alone and when levofloxacin was given on the sixth day after lithium steady-state levels were achieved. The third group compared the Pk parameters of lithium when lithium was given alone for 8 days and levofloxacin was given on days 6, 7, and 8 along with lithium. Apart from this, creatinine levels were also measured to detect nephrotoxicity effects because of this co-administration. It was found that there was increase in lithium levels in all three groups. The increase was significant when a single dose of levofloxacin was administered with steady-state level of lithium (C(max) of lithium: 2.54 ± 0.15 vs 2.79 ± 0.12 mm, P < 0.001 and AUC(0-α) of lithium: 24.36 ± 3.68 vs 31.88 ± 4.83 mmol/mL h, P < 0.001). The increase in lithium levels was also significant when levofloxacin was coprescribed for 3 days after lithium steady-state levels were achieved (C(max) increased from 2.72 ± 0.29 to 3.96 ± 0.29 mm, P < 0.001 and AUC(0-α) increased from 27.1 ± 4.96 to 42.64 ± 4.94 mmol/mL h). Levofloxacin increases lithium levels when they are co-administered, and this interaction might be clinically significant as they may be coprescribed.

Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults

The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

Levofloxacin reduces inflammatory cytokine levels in human bronchial epithelia cells: implications for aerosol MP-376 (levofloxacin solutionfor inhalation) treatment of chronic pulmonary infections

Inflammation resulting from chronic bacterial infection in the lung contributes to long-term pulmonary complications in chronic pulmonary infections such as cystic fibrosis. Aerosol administration of levofloxacin as in the form of the investigational formulation MP-376 results in higher concentrations in lung tissues that are higher than those that can be attained with oral or intravenous dosing of levofloxacin. The objective of this study was to evaluate the effect of high concentrations of levofloxacin achieved with aerosol administration of MP-376 on proinflammatory cytokine secretion by immortalized human bronchial epithelia cells in vitro. Additionally, we investigated the potential mechanisms of the immunomodulatory effect of levofloxacin. In vitro studies in human lung epithelial cell lines showed that levofloxacin led to a dose-related reduction in IL-6 and IL-8 concentrations, with 300 μg mL(-1) resulting in the reduction of levels of IL-6 by fourfold and IL-8 by twofold (P<0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8. Levofloxacin treatment did not affect the cytokine mRNA level and nuclear factor-κB-dependent promoter activity. These findings suggest that high concentrations of levofloxacin obtained in pulmonary tissues following the administration of aerosol MP-376 may provide additional benefits in patients with chronic pulmonary infections that are independent of its antibacterial properties.

Intensified treatment with high dose Rifampicin and Levofloxacin compared to standard treatment for adult patients with Tuberculous Meningitis (TBM-IT): protocol for a randomized controlled trial

BackgroundTuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin.Methods/DesignA randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events.DiscussionCurrently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration.Trial registrationInternational Standard Randomised Controlled Trial Number ISRCTN61649292

Evaluation by Monte Carlo simulation of levofloxacin dosing for complicated urinary tract infections caused by Escherichia coli or Pseudomonas aeruginosa

We evaluated, by Monte Carlo simulation, 500-mg once-daily, 100-mg thrice-daily, 200-mg twice-daily, and 200-mg thrice-daily dose regimens of levofloxacin (LVFX), for the ratio of area under the concentration-time curve for 24 h (AUC(0-24)) to minimum inhibitory concentration (MIC) (AUC(0-24)/MIC) and the ratio of maximum plasma concentration (C(max)) to MIC (C(max)/MIC), which predict microbiological outcomes, and the C(max)/MIC, which inhibits fluoroquinolone resistance selection, in complicated urinary tract infections (UTIs) with Escherichia coli or Pseudomonas aeruginosa. Monte Carlo simulation was performed for 10000 cases using the pharmacokinetic data of patients with complicated UTIs and the LVFX MIC distributions for E. coli or P. aeruginosa clinical strains. The probabilities of achieving the AUC(0-24)/MIC target (66.2-67.9%) and the C(max)/MIC target (64.5-67.5%) to eradicate E. coli were similar among the 4 regimens. In eradication of P. aeruginosa, the 200-mg thrice-daily and the once-daily dose regimens produced higher probabilities of achieving the AUC(0-24)/MIC target (57.5%) and C(max)/MIC target (55.1%), respectively. For the probabilities of achieving the C(max)/MIC targets that prevent the emergence of fluoroquinolone resistance, the once-daily dose regimen (66.8%) did not differ from the other multiple-dose regimens (62.3-66.2%) in E. coli, whereas the former regimen (44.2%) was superior to the latter regimens (10.8-31.7%) in P. aeruginosa. The 500-mg once-daily dose regimen of LVFX, which produced the larger AUC(0-24) and higher C(max), could ensure the efficacy of eradication of uropathogens and reduce the risk of fluoroquinolone resistance selection in complicated UTIs.

Aqueous and Vitreous Penetration of Linezolid and Levofloxacin After Oral Administration

To evaluate the time course of drug concentrations achieved in aqueous (AQ), vitreous (V), and serum (S) compartments after oral administration of linezolid and levofloxacin. Randomized, clinical trial. Clinical practice. Sixteen patients (16 eyes) undergoing vitrectomy who had not had a prior pars plana vitrectomy in the study eye were randomly assigned to one of 4 groups. AQ, V, and S samples were obtained from all subjects after single concomitant doses of linezolid 600 mg and levofloxacin 750 mg between 1 and 12 h before the procedure: group A = 1-3 h; group B = 3-6 h; group C = 6-9 h; group D = 9-12 h. AQ, V, and S concentrations of linezolid and levofloxacin. Overall mean concentrations ± standard deviation (μg/mL) achieved by linezolid in AQ, V, and S compartments were 3.32 ± 2.06, 2.98 ± 1.87, and 7.91 ± 3.94, respectively. Overall mean concentrations ±standard deviation (μg/mL) achieved by levofloxacin in AQ, V, and S compartments were 2.19 ± 1.92, 1.95 ± 1.27, and 7.38 ± 3.47, respectively. Single concomitant doses of linezolid and levofloxacin achieved AQ and V concentrations above the minimum inhibitory concentration for 90% of common ocular gram-positive and gram-negative pathogens up to 12 h after administration. The combination of linezolid and levofloxacin represents a viable option for the prophylaxis and management of endophthalmitis.

Permeability and Concentration of Levofloxacin in Epithelial Lining Fluid in Patients With Lower Respiratory Tract Infections

The purpose of the study was to assess the bactericidal effects of a single oral dose of levofloxacin (LVFX) by examining the concentration of LVFX in alveolar epithelial lining fluid (ELF) from patients with lower respiratory tract infections (LRTI). Forty patients with LRTI took 500 mg of LVFX and then received a fiberoptic bronchoscopic procedure randomly 1, 4, 8, 12, or 24 hours following dosing. Bronchoalveolar lavage fluid and blood were collected at the time of the bronchopulmonary procedure, and the LVFX concentration was determined. The mean peak concentrations of LVFX in plasma and ELF were achieved at 1.5 hours (4.07 mg/L) and 1 hour (3.44 mg/L), respectively. The AUC(24h) samples were 50.12 mg . h/L and 34.51 mg . h/L, respectively. The permeability of LVFX, which was estimated based on the ratio of LVFX concentration in tissue fluids to that in plasma, was 0.78 on average across all time points. After a single dose of LVFX in patients with LRTI, the drug rapidly distributed into bronchopulmonary tissue, thereby suggesting this dose is capable of achieving the concentration in target organs required for bactericidal efficacy.