Dose Of Levofloxacin Research Articles

Comparative pharmacokinetics of levofloxacin in the saliva and blood plasma of patients with pneumonia

BACKGROUND: Levofloxacin concentrations do not always reach desired levels when administered at a standard dose; therefore, measuring levofloxacin levels in the blood plasma or other alternative matrices, such as the saliva, can help clinicians make informed decisions concerning the dosage and mode of administration. Saliva, as an object of research, is of particular interest due to the simplicity and non-invasiveness of sampling for analysis.
 AIM: This study aimed to determine the comparative pharmacokinetics of levofloxacin in the blood plasma and saliva of patients with community-acquired pneumonia (CAP) and assess the possibility of using saliva as an alternative sampling matrix in pharmacokinetic studies.
 MATERIALS AND METHODS: Levofloxacin concentration in the blood plasma and saliva of patients with CAP and volunteers was determined using high-performance liquid chromatography on an Agilent 1200 liquid chromatography (Agilent, USA) with an ultraviolet detector. Sample preparation of bioassays was performed using protein precipitation. Patients and volunteers took 1 tablet (500 mg dose) of levofloxacin per os in the morning, on an empty stomach. Blood and saliva samples were taken at the initial blood sample and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after taking the drug. The pharmacokinetic parameters were determined, namely Cmax as the peak concentration of the drug; Тmax as the time-to-peak concentration; AUC0t as the area under the pharmacokinetic curve in the range from 0 to the last experimental point on the curve; AUC0 as the total area under the pharmacokinetic curve from zero to infinity; t1/2 as half-life period; MRT as mean residence time of the drug in the blood (h); Cl/F as clearance; and Vss/F as the total distribution volume.
 RESULTS: The maximum blood plasma and saliva concentration of patients was reached 1 h after taking the drug and amounted to Сmax=5.982.89 g/ml and Сmax=4.413.83 g/ml, respectively. Additionally, the maximum concentrations in blood plasma and saliva were recorded 1 h after taking the drug as 5.523.07 g/ml and 3.250.85 g/ml, respectively, in healthy volunteers. The correlation coefficient (r) between the mean values of the levofloxacin concentrations in the blood plasma and the saliva of patients with CAP was 0.953 and that of healthy volunteers was 0.977.
 DISCUSSION: Pharmacokinetic parameters were calculated based on blood plasma and saliva concentrations. Their comparative analysis revealed almost the same absorption rate from the gastrointestinal tract in patients and healthy volunteers. Correlation-regression analysis revealed a high correlation between the average values of Cmax in saliva and plasma both in the patient (r=0.96) and healthy volunteer group (r=0.98).
 CONCLUSIONS: With statistically significant differences in the areas under pharmacokinetic curves in blood plasma and saliva, the remaining pharmacokinetic parameters of saliva and blood plasma did not significantly differ between patients with CAP and healthy volunteers. A significant direct correlation was revealed between the mean concentration and pharmacokinetic parameters in saliva and blood plasma in both groups. The study demonstrated the possibility of using saliva as a biomaterial in the study of levofloxacin pharmacokinetics.

Anti-Mutant Efficacy of Combination Therapy with Doripenem and Levofloxacin: <i>In Vitro</i> Model Studies with <i>Pseudomonas Aeruginosa</i>

Relevance. The tendency to a decrease in sensitivity of bacterial agents to old antibiotics, as well as the slowdown in creation of new medications, dictate the need to develop effective approaches to combat bacterial resistance.Aim. Evaluation of the applicability of a pharmacokinetically-based approach to predicting anti-mutant effectiveness of combined therapy with doripenem and levofloxacin against gram-negative bacteria Pseudomonas aeruginosa.Material and methods. A collection strain of Pseudomonas aeruginosa was used in the study. The values of MPC (mutant prevention concentration) of the combination of doripenem and levofloxacin were evaluated at a ratio of their concentrations equal to therapeutic ratios of the area under the pharmacokinetic curve in the in vitro dynamic model. 5-day treatments with clinical doses of doripenem and levofloxacin individually and in combination were simulated. Bacteria-containing medium was sampled during the experiments and plated on agar media containing 2MIC of each antibiotic.Results. The MPCs of doripenem and levofloxacin decreased 4 times when used in combination compared to MPC values when used separately. P.aeruginosa population was enriched with resistant mutants during monotherapy with each medication; the number of the bacteria did not decrease or even increased by the end of observation period. The use of doripenem/levofloxacin combination completely prevented development of resistance to both drugs in P.aeruginosa. The observed anti-mutant effect of antibiotic combination was consistent with higher (compared to monotherapy) values of the time during which the concentration of the antibiotic exceeded MPC (T>MPC).Conclusion. The anti-mutant effectiveness of combined therapy with doripenem and levofloxacin increased with the decrease in the values of MPC of antibiotics when used simultaneously, which consequently led to the increase in the values of T>MPC. Obtained results confirm the applicability of a pharmacokinetically-based approach to the estimation of MPC of combined antibiotics for predicting anti-mutant effectiveness of combination therapy in the treatment of infections caused by gram-negative bacteria.

Population pharmacokinetics of oral levofloxacin in healthy volunteers and dosing optimization for multidrug-resistant tuberculosis therapy.

Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32Lh-1 (22.6%), apparent central volume of distribution 35.8L (45.2%), apparent peripheral volume of distribution 39.7L, intercompartmental clearance 40.6Lh-1 (43.8%), absorption rate constant 7.45h-1 (150%), mean absorption transit time 0.355h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5mg L-1 , while a dose of 1500mg was required for strains with an MIC of 1mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.

DRUG UTILIZATION REVIEW OF FLUOROQUINOLONES ANTIBIOTICS BY USING PRESCRIBING INDICATORS &amp; COMPARISON OF DEFINE DAILY DOSE &amp; PRESCRIBED DAILY DOSE IN OUTPATIENTS

Background: The increase in antibiotic resistance is new developing threat to healthcare system. Irrational drug use, polypharmacy and the current epidemic of bacterial resistance is attributed to the increase in use of antibiotics. The aim of the current study is to evaluate the difference between defined daily dose and prescribed daily dose of fluoroquinolones antibiotics.&#x0D; Methodology: Quantitative observational, retrospective study was carried out to measure the use of antibiotics, specifically Fluoroquinolones at northern region of Punjab, Nowshera Virkan, Tehsil of Gujranwala District, Pakistan. Total 300 patients were enrolled in this study. Data were collected from the patients of all age from either sex, by prescription review. Data included the drug name, strength and quantity.&#x0D; Results: 300 prescriptions were reviewed to evaluate the prescription pattern of fluoroquinolones in outpatients. Among the prescribing indicators, the average number of drugs per prescription was 4.5. Out of 300 prescriptions maximum number of drugs per prescription was 8 in only one prescription and minimum one drug was prescribed in 28(9.3) prescriptions. The number of prescriptions that contains the drugs without generic were 71(23.7) and which contains one drug with generic were 203(67.7). Encounter with antibiotic prescribed were 79.3%. Encounter with injection prescribed was 5.3%. All drugs were prescribed from Essential drug list (EDL). Ciprofloxacin was the most commonly prescribed followed by Levofloxacin and Moxifloxacin. Defined daily dose and prescribed daily dose of Ciprofloxacin were same (1) but the prescribed daily dose of levofloxacin (0.5) was higher than the Defined Daily Dose (1).&#x0D; Conclusion: Irrational use of drugs, polypharmacy, over prescribing of antibiotics and brand prescribing were observed during the study. Lack of knowledge and nonadherence to the prescribing indicators are the major factors that contribute towards the irrational drug prescribing that ultimately lead towards the antibiotic resistance.

Levofloxacin pharmacokinetics and tissue residue concentrations after oral administration in Bilgorajska geese

ABSTRACT 1. The aim of this study was to assess the pharmacokinetics of levofloxacin, a third-generation fluoro-quinolone antimicrobial drug, in geese (n = 26) after either single intravenous or oral administration, and to evaluate the depletion profile in goose muscle, heart, liver, kidney and lung after a single oral dose. 2. The pharmacokinetic study involved 16 geese which were randomly divided into two groups (n = 8/group), the first received levofloxacin (2 mg/kg) intravenously while the second was treated with orally (5 mg/kg). The tissue depletion study involved 10 geese which were dosed orally (5 mg/kg) and two animals were killed at different time-points in order to collect the selected tissues. Levofloxacin was quantified in all the matrices tested by a validated high-performance liquid chromatography (HPLC) method, using a spectrofluorimetric detector. The pharmacokinetics were analysed using a non-compartmental model. 3. Plasma concentrations were quantified after up to 24 h in animals administered intravenously and up to 48 h after oral treatment. Levofloxacin was rapidly absorbed after oral administration (Tmax = 0.38 h) showing high bioavailability (95.57 ± 20.61%). The drug showed a moderate volume of distribution (1.40 ± 0.28 ml/g) and rapid clearance (0.28 ± 0.06 ml/g/h). No statistical differences in estimates were found between the two different administration methods (P > 0.05). Drug residues were highest at 6 h and decreased constantly up to 48 h in all the selected tissues. Liver and kidney had the highest levofloxacin concentrations. 4. According to the pharmacokinetic/pharmacodynamic surrogate index (AUC/MIC) the levofloxacin dose regimen (after oral administration) used in the present study could be active against bacteria at a minimum inhibitory concentration (MIC) > 0.24 μg/ml in geese. In addition, drug accumulation in the liver might be controlled using an estimated preliminary withdrawal time of 90 h.

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy.

To determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT). All necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC24h/MIC ≥50 for Gram-positive and AUC24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients. No conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2mg/L. The successful dose (1750mg on day 1, then 1500mg q 24h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750mg q 24h was sufficient to attain PTA target of ~90% at the MIC of 2mg/L for Streptococcus pneumoniae. Levofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.

Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model.

The use of antibiotics is a vital means of treating infections caused by the bacteria Bacillus (B.) anthracis. Importantly, with the potential future use of multidrug-resistant strains of B. anthracis as bioweapons, new antibiotics are needed as alternative therapeutics. In this blinded study, we assessed the protective efficacy of teixobactin, a recently discovered antibiotic, against inhalation anthrax infection in the adult rabbit model. New Zealand White rabbits were infected with a lethal dose of B. anthracis Ames spores via the inhalation route, and blood samples were collected at various times to assess antigenemia, bacteremia, tissue bacterial load, and antibody production. Treatments were administered upon detection of B. anthracis protective antigen in the animals’ sera. For comparison, a fully protective dose of levofloxacin was used as a positive control. Rabbits treated with teixobactin showed 100% survival following infection, and the bacteremia was completely resolved by 24–48 h post-treatment. In addition, the bacterial/spore loads in tissues of the animals treated with teixobactin were either zero or dramatically less relative to that of the negative control animals. Moreover, microscopic evaluation of the tissues revealed decreased pathology following treatment with teixobactin. Overall, these results show that teixobactin was protective against inhalation anthrax infection in the rabbit model, and they indicate the potential of teixobactin as a therapeutic for the disease.

Pharmacokinetics of levofloxacin after single intravenous and oral administration, and its interaction with sucralfate in mixed-breed dogs

The study aims to establish the plasma pharmacokinetic parameters of levofloxacin in mixed-breed dogs, at a single dose of 5 mg/kg, intravenously, orally only and orally with sucralfate pre-treatment (1 g per animal), to evaluate its influence on antimicrobial absorption. Concentrations of levofloxacin in plasma were determined using high-performance liquid chromatography (HPLC) with fluorescence detection. After iv of levofloxacin, the mean (±SD) of AUC0–24, Vz, t½λz and MRT, was 19.05 ± 6.4 µg-h/ml, 2.43 ± 0.5 L/kg, 7.93 ± 1.41 hours and 8.7 ± 1.5 hours, respectively. After oral administration, the C max, t½λz and bioavailability were 1.95 ± 0.7 µg/ml, 7.65 ± 1.38 hours and 71.93 ± 9.75%, respectively. In animals given an oral dose of levofloxacin with sucralfate pre-treatment, there was a significant decrease (p < 0.05) in C max (0.57 ± 0.23 µg/ml), AUC (5.73 ± 2.26 µg-h/ml) and bioavailability (31.92 ± 14.19%). In the dogs studied, it is suggested that the dose 5 mg/kg of levofloxacin for both routes is inadequate to meet PK–PD targets for susceptible bacteria using breakpoints established by the Institute of Clinical and Laboratory Standards (CLSI).

The African Green Monkey Model of Pneumonic Plague and US Food and Drug Administration Approval of Antimicrobials Under the Animal Rule.

Additional treatment options for pneumonic plague, the most severe form of infection by Yersinia pestis, are needed, as past US Food and Drug Administration (FDA) approvals were not based on clinical trials that meet today's standards, and multiple drugs are sought to counter resistance or use in special populations. Due to the sporadic nature of outbreaks and the low number of pneumonic cases of disease, we sought FDA approval of antimicrobials for treatment under the Animal Efficacy Rule, where efficacy can be demonstrated in 1 or more well-characterized animal models that sufficiently represent human disease. A model was developed in African green monkeys (AGMs) after challenge with a lethal dose of Y. pestis delivered as an aerosol, in 4 independent studies in 3 laboratories. The primary data points were bacteremia (daily), body temperature and heart rate (continuously monitored by telemetry), and survival. In antimicrobial efficacy studies, human-equivalent doses of gentamicin, ciprofloxacin, levofloxacin, and doxycycline were administered upon fever onset for 10 days. Disease in AGMs was similar to case reports of human disease. Fever was determined to be a reliable sign of disease and selected as a treatment trigger. Gentamicin was 60%-80% effective depending on the dose given to animals. Ciprofloxacin and levofloxacin were found to be >90% efficacious. These data were submitted to FDA and plague indications were approved. Doxycycline was less effective. The AGM model of pneumonic plague is reproducible, well-characterized, and mimics human disease. It has been used to support plague indications for fluoroquinolones and to test the efficacy of additional antimicrobials.

Urine colorimetry for levofloxacin pharmacokinetics and personalized dosing in people with drug-resistant tuberculosis.

Background:Levofloxacin is a preferred drug for multidrug-resistant (MDR)-tuberculosis (TB) with bactericidal activity that correlates with the pharmacokinetic exposures of serum peak concentration (Cmax) and total area under the concentration time curve (AUC0-24). Pharmacokinetic exposures can be measured to personalize dosing to reach targets, but this practice requires venepuncture, chromatographic or mass spectrometry equipment, and technical expertise. We sought to demonstrate the accuracy of using urine colorimetry as a more feasible estimation of levofloxacin exposure.Method:A colorimetric method using bromocresol green was tested on spiked urine samples with levofloxacin measured using a spectrophotometer. This method was tested in urine samples of healthy volunteers given one 750 mg dose of levofloxacin with urine collected at 0–4 h, 4–8 h, and 8–24 h intervals, and concomitant serum samples were collected and analyzed by high-performance liquid chromatography. Validation of this assay was done in a cohort of people living with human immunodeficiency virus (PLWH), initiating a levofloxacin containing MDR-TB regimen.Results:Urine colorimetry was reproducible in spiked samples and the calibration was curve linear for levofloxacin concentrations ranging from 7.8 μg/ml to 250 μg/ml, with r = 0.98. In healthy volunteers, correlation between urine absorbance values and serum AUC0-24 was highest in urine collected between 4 and 8 h (r = 0.91, P = 0.01), yet in PLWH, urine collected between 0 and 4 h had highest correlation (r = 0.66, P = 0.05). The area under the receiver operating characteristics curve was >0.8 in the derivation, as well as the validation cohort for the urine absorbance values identifying people with total serum exposure below target.Conclusion:Urine colorimetry was highly sensitive in predicting target serum concentrations. Colorimetric methods to determine levofloxacin in urine may improve the feasibility of therapeutic drug monitoring and personalized dose adjustment in TB endemic settings.

ОСТРАЯ ТОКСИЧНОСТЬ И СРАВНИТЕЛЬНАЯ ТЕРАПЕВТИЧЕСКАЯ ЭФФЕКТИВНОСТЬ ЛЕВОФЛОКСАЦИНА ПРИ ЭКСПЕРИМЕНТАЛЬНОМ КОЛИБАКТЕРИОЗЕ ЦЫПЛЯТ

Development and improvement of treatment modes for colibacillosis in chickens is very important as this disease is rather prev-alent in bird population. Fluoroquinolones are drugs that are very effective in treating bacterial infections, associated with Gram- negative microorganisms, in animals. The goal of the present research was to evaluate acute toxicity of Levofloxacin in chickens and to study its comparative therapeutic effi-cacy in experimental colibacillosis of chick-ens. For the experiment aimed at evaluating acute toxicity of Levofloxacin all the chick-ens were assigned to a total of 18 groups, 10 chickens were assigned to each group. The drug was administered by intraperitoneal injection at a dose of 100 to 950 mg/kg body weight. In our research median lethal dose (LD50) of Levofloxacin, in case of intraperi-toneal introduction to chickens, was as high as 470 mg/kg body weight (276.4–799 mg/kg body weight). For the experiment aimed at studying comparative therapeutic efficacy of Levofloxacin in experimental colibacillosis all the chickens were assigned to a total of 8 groups, 25 chickens were assigned to each group. In the course of the experiment every chicken was challenged with Escherichia coli, by intraperitoneal introduction of 150 million CFUs (E. coli had been cultured in suspension for 24 hours). Antimicrobial drugs (Levofloxacin, Enrofloxacin, Colistin, Ditrim, Doxycycline, Chloramphenicol) were first administered 24 hours before the challenge, at a concentration of 200 mg/L, via drinking water. The treatment continued 5 days. The chickens were monitored 3 weeks. The results of the experiments show the high therapeutic effect in cases of Levofloxacin (100%) and Enrofloxacin (92%). Administration of other antimicrobial drugs did not lead to the expected results. The survival rate was in the range 12 to 20%

Obesity is not strongly associated with increased risk for febrile neutropenia during levofloxacin prophylaxis in patients with hematological malignancies receiving intermediate-risk myelosuppressive chemotherapy.

Levofloxacin given at a standard dose of 500 mg daily is recommended for antibacterial prophylaxis in patients receiving myelosuppressive chemotherapy. Obese patients have been shown to exhibit enhanced clearance of levofloxacin and may be at risk for prophylactic failure. This single center, retrospective cohort study from June 2014 to May 2017 evaluated adult patients with estimated creatinine clearance ≥50 mL/min receiving their first cycle of a National Comprehensive Cancer Network defined intermediate-risk regimen. Primary endpoint was incidence of febrile neutropenia. Secondary endpoints included 30-day mortality and the correlation between estimated levofloxacin area under the concentration-time curve and rates of febrile neutropenia. Febrile neutropenia occurred in 26 patients: 12 (35.3%) obese and 14 (21.9%) non-obese (P = 0.16). Six (23.1%) of these patients required intensive care, but there were no deaths within 30 days of a febrile neutropenia event. Estimated creatinine clearance was similar between obese and non-obese patients (median 97.5 vs. 91.8 mL/min, P = 0.39), as was estimated levofloxacin area under the concentration-time curve (median 85.6 vs. 90.8 mg×h/L, P = 0.39). There were no significant associations between body weight-related variables - total body weight (median 83.4 vs. 80.6 kg, P = 0.51), body mass index (mean 29.6 vs. 26.8 kg/m2, P = 0.35), or body surface area (1.98 vs. 1.99 m2, P = 0.68) - and febrile neutropenia in this cohort of patients with similar renal function. Obesity should not be a justification for more aggressive levofloxacin dosing schemes when used for febrile neutropenia prophylaxis.

Evaluation of levofloxacin utilization in intensive care units of tertiary care hospital: a retrospective observational study

The emergence of antibiotic-resistant bacteria is a major problem throughout the world, and rational use of antibiotics is, therefore, very important. Levofloxacin is one of the most commonly used antibiotics due to its wide spectrum antimicrobial activity and low potential for toxicity. Drug use evaluation (DUE) focuses on evaluation and improvement of drug prescribing patterns to achieve optimal patient outcomes. The study was designed to evaluate levofloxacin prescribing patterns, including appropriate indication, dose, dose adjustment in renal impairment, and duration of treatment, by conducting a DUE program in intensive care units (ICUs). A retrospective observational study was conducted over a 4-month period. A total of 222 patients receiving levofloxacin (a broad-spectrum fluoroquinolone) were identified. Patients were primarily recruited from ICUs. The present study showed that levofloxacin was used empirically in most patients (78.4%). The most common indication for levofloxacin use was community-acquired pneumonia, observed in 75 patients (33.8%). Most commonly, the daily dose of levofloxacin was 500 mg or 750 mg, the frequency of administration was twice (27%) or once daily (73.0%), and the duration of treatment with levofloxacin was 7–10 days (67.6%). Inappropriate use of levofloxacin was observed in some patients (27.9%), the greatest proportion of which was attributed to absence of culture and sensitivity test (61.3%), followed by inappropriate indications (46.8%). Our study indicated that there is substantial scope for improvement in prescribing patterns at Damanhour Medical National Institute that could be achieved by adhering to standard guidelines of treatment and restriction policies to promote rationality of drug use.

Levofloxacin Induced Stomatitis: A Case Report

Fluoroquinolones have many adverse effects include the gastrointestinal tract and the central nervous system, phototoxicity, and dermal toxicity. Levofloxacin has favorable adverse reaction profiles compared to other fluoroquinolones. Among the reported dermal toxicity there are few reports of toxic epidermal necrosis (TEN) in association with levofloxacin usage. However, there is no published study on levofloxacin induced stomatitis. Stomatitis is characterized by pain, inflammation, and ulceration in the oral cavity. A 36-year-old man was referred to the hospital for ‘painful oral swelling and ulceration’. Before the admission due to fever and productive cough, 750 mg levofloxacin were prescribed for him. After 2 days of consumption, the patient experiences painful ulcerative and erythema lesions in the oral cavity that consistent with stomatitis. Due to the possibility of a drug reaction, levofloxacin was discontinued and no other antibiotic was used. Oral lesions were managed with a mouthwash and after 5 days, lesions recovered. To the best of our knowledge, this is the first case who developed stomatitis after two dose of levofloxacin and recovered just with topical therapy and without any systemic treatment. Caution is advised while administering these drugs.

124. Impact of Levofloxacin MIC on Outcomes with Levofloxacin Step-down Therapy in Enterobacteriaceae Bloodstream Infections

BackgroundThe Clinical and Laboratory Standards Institute reduced the levofloxacin minimum inhibitory concentration (MIC) breakpoint from ≤2 to ≤0.5 mg/L for Enterobacteriaceae in 2019 guidelines. The reduction is based on Monte Carlo simulations for a levofloxacin dose of 750 mg daily. The aim of this study was to determine whether there was a difference in clinical outcomes in the treatment of Enterobacteriaceae bacteremia with levofloxacin step-down therapy retrospectively comparing patients with isolates with low levofloxacin MICs (≤0.5 mg/L) to high MICs (1–2 mg/L).MethodsThis retrospective, two-center cohort study included patients ≥18 years of age with a monomicrobial Enterobacteriaceae bacteremia with a levofloxacin MIC ≤2 mg/L from March 2017 through December 2018. Patients had to have received treatment with ≥3 days of levofloxacin step-down therapy, initial intravenous therapy with an agent active against the isolated organism, and total duration not exceeding 16 days from first negative blood culture. A subset of patients whose isolates had low levofloxacin MICs were randomly selected for comparison to all patients with high levofloxacin MICs in a 3:1 ratio. The primary outcome was a composite endpoint of recurrence and mortality within 30 days of completion of the antibiotic course. Secondary outcomes included post-culture length of stay (LOS) and 30-day readmission rate.ResultsThirty-three patients with high MIC and 99 with low MIC were included. Urinary source was predominant and occurred in 44% of patients, and Escherichia coli was the infecting organism in 48%. Over 80% of patients experienced source resolution or control. The composite endpoint occurred in 8.1% of the low MIC group and 9.1% of the high MIC group (P = 0.856). Median LOS was 4.9 days (IQR 3.7–8.0) in the low MIC group and 4.3 days (IQR 3.2–6.8) in the high MIC group (P = 0.384), and readmission rate was 17.2% in the low MIC group and 15.2% in the high MIC group (P = 0.787).ConclusionThere was no between-group difference in the primary outcome of recurrence and mortality, with a low overall event rate and short LOS post-culture. These results suggest that levofloxacin effectiveness may be sustained in patients with MICs of 1 or 2 despite levofloxacin not meeting susceptibility criteria by new definitions.Disclosures All authors: No reported disclosures.

The effect of levofloxacin on the lung microbiota of laboratory rats

Aim: The aim of this study was to investigate the short-term effect of levofloxacin on the microbiota of healthy lungs.Material and methods: Male F344 rats received either no levofloxacin (n = 9), intravenous levofloxacin (n = 12), oral levofloxacin (n = 12), or subcutaneous levofloxacin (n = 14). Rats received a clinically applicable dose (5.56 mg/kg) of levofloxacin via the assigned delivery route once daily for three days. On day four, lung tissue was collected and the lung microbiota composition was investigated using 16S ribosomal RNA gene sequencing.Results: Untreated lungs showed a microbiota dominated by bacteria of the genera Serratia. After treatment with levofloxacin, bacteria of the genus Pantoea dominated the lung microbiota. This was observed for all routes of antibiotic administration, with a significant difference compared to no-antibiotic control group (PERMANOVA: P < 0.001; homogeneity of dispersions: P = 0.656).Conclusion: Our study is the first to demonstrate the effects of levofloxacin therapy on lung microbiota in laboratory rats. Levofloxacin treatment by any route of administration leads to profound changes in the rat lung microbiota, resulting in the predominance of bacteria belonging to the genus Pantoea. Further studies regarding the role of long-term application of broad spectrum antibiotics on induction of lung, allergic and autoimmune diseases are indicated.

Dexamethasone improves therapeutic outcomes in a preclinical bacterial epididymitis mouse model.

Can dexamethasone improve infertility-related cauda epididymidal tissue damage caused by bacterial epididymitis? Dexamethasone in addition to anti-microbial treatment effectively reduces long-term deleterious epididymal tissue damage by dampening the host's adaptive immune response. Despite effective anti-microbial treatment, ~40% of patients with epididymitis experience subsequent sub- or infertility. An epididymitis mouse model has shown that the host immune response is mainly responsible for the magnitude of epididymal tissue damage that is fundamentally causative of the subsequent fertility issues. Bacterial epididymitis was induced in male mice by using uropathogenic Escherichia coli (UPEC). From Day 3 after infection onwards, mice were treated with daily doses of levofloxacin (20mg/kg, total n= 12 mice), dexamethasone (0.5mg/kg, total n= 9) or both in combination (total n= 11) for seven consecutive days. Control animals were left untreated, i.e. given no interventional treatment following UPEC infection (total n= 11). Half of the animals from each group were killed either at 10 or 31days post-infection. A mouse model of induced bacterial epididymitis was applied to adult male C57BL/6J mice. At the respective endpoints (10 or 31days post-infection), epididymides were collected. Effectiveness of antibiotic treatment was assessed by plating of epididymal homogenates onto lysogeny broth agar plates. Overall tissue morphology and the degree and nature of tissue damage were assessed histologically. Quantitative RT-PCR was used to assess local cytokine transcript levels. Blood was drawn and serum analysed for systemic IgG and IgM levels by ELISA. In addition, correlation analyses of clinical data and serum-analyses of IgG and IgM levels in patients with epididymitis were performed. The addition of dexamethasone to the standard anti-microbial treatment did not further worsen epididymal tissue integrity. In fact, an obviously dampened immune response and reduced tissue reaction/damage was observed at both 10 and 31days post-infection following combined treatment. More specifically, epididymal duct continuity was preserved, enabling sperm transit. In contrast, in untreated or antibiotic-treated animals, damage of the epididymal duct and duct constrictions were observed, associated with a lack of cauda spermatozoa. In line with the bacteriostatic/bactericidal effect of levofloxacin (alone as well as in combination), local cytokine transcript levels were significantly and similarly reduced in animals treated with levofloxacin alone (P< 0.01) or in combination with dexamethasone (P< 0.05) compared to UPEC-infected untreated animals. Interestingly, the addition of dexamethasone to the anti-microbial treatment induced a unique dampening effect on adaptive immunity, since systemic IgG and IgM levels as well as the pan-T cell marker CD3 were reduced at both 10 and 31days post-infection. Breeding studies to address the fertility-protecting effect of the combined treatment were not possible in the experimental animals because the vas deferens was ligated (model specific). Whereas innate immunity is necessary and involved in acute bacterial clearance, adaptive immunity seems to be responsible for long-term, subclinical immunological activities that may negatively affect the pathogenesis of bacterial epididymitis even after effective bacterial eradication. These effects can be reduced in mice by the additional treatment with dexamethasone. This immunological characteristic of bacterial epididymitis shows similarities to the Jarisch-Herxheimer reaction known from other types of bacterial infection. The study was supported by grants from the Deutsche Forschungsgemeinschaft, Monash University and the Medical Faculty of Justus-Liebig University to the International Research Training Group on 'Molecular pathogenesis of male reproductive disorders' (GRK 1871). R.W., K.L.L. and M.P.H. were supported by grants from the National Health and Medical Research Council of Australia (ID1079646, ID1081987, ID1020269 and ID1063843) and by the Victorian Government's Operational Infrastructure Support Program. The authors have no conflicts of interest to declare. No clinical trial involved.

CASE REPORT ON SEIZURE WITH CO ADMINISTRATION OF LEVOFLOXACIN AND THEOPHYLINE

Case Summary: An 84-year-old man was admitted to the hospital due to seizure episodes. One week before the patient was admitted to the same hospital with complaints of COPD exacerbation and was discharged with a prescription of levofloxacin, theophylline ceftriaxone, pantaprazole, montelukast, methylprednisolone, budesonide nebulization, ipratropium bromide nebulization, and syrup codylex. After receiving one dose of oral levofloxacin, the patient experienced a seizure. The patient was hyperglycaemic at the time of admission and had no history of a seizure disorder. Discussion: Here the cause of seizure could be a drug-drug interaction (between theophylline and levofloxacin) with CYP1A2 substrates with no epileptogenic effects which could augment the concentration of levofloxacin and consequently results in seizures. In spite of that, it has to be kept in mind that the drug-drug interactions originate at various pharmacodynamic and pharmacokinetic levels and that drugs CYP affinities are rarely completely CYP-specific. Thus levofloxacin may have drug interactions at the level of CYPs other than CYP1A2. Conclusion: the clinicians are advised to closely monitor the possibility of seizures in COPD patients who+ are taking both levofloxacin and theophylline. The physicians should also be encouraged to use the techniques of TDM to individualize the dose of narrow therapeutic drugs to avoid serious adverse effects.

Interim Study: Comparison Of Safety And Efficacy of Levofloxacin Plus Colistin Regimen With Levofloxacin Plus High Dose Ampicillin/Sulbactam Infusion In Treatment of Ventilator-Associated Pneumonia Due To Multi Drug Resistant Acinetobacter.

Due to the emerging antibiotic resistance of Acinetobacter, which is the leading cause of ventilator-associated pneumonia (VAP) in critically ill patients, there is an urgent need for studies comparing various antibiotic regimens for its treatment. In this single blinded randomized clinical trial, adult patients with VAP due to multi drug resistant Acinetobacter (MDRA), were randomly assigned to receive 9×109 unit loading dose of colistin followed by 4.5×109 unit intravenously twice daily plus 750 mg intravenous levofloxacin daily or continuous infusion of ampicillin/sulbactam, 24g daily plus 750mg IV levofloxacin daily. Dose and dosing interval were adjusted according to serum creatinine levels during the study. Clinical and microbiological cure, inflammatory biomarkers, and possible adverse effects were recorded in participants. Twenty-nine patients were recruited (14 in colistin and 15 in ampicillin/sulbactam groups). Three patients were excluded in each group. Clinical response occurred in 3 (27%) and 10 (83%) in colistin and ampicillin-sulbactam arms, respectively (P = 0.007). Nephrotoxicity happened in 6 (54%) and 1 (8%) of cases in colistin and ampicillin-sulbactam groups, (P = 0.016). 14-day and 28-day survival rate were significantly higher in ampicillin-sulbactam group compared to colistin arm with P values of 0.002 and 0.049, respectively. This study revealed that levofloxacin plus high dose ampicillin/sulbactam as continuous infusion is more effective than levofloxacin plus colistin in patients with MDR Acinetobacter VAP with significantly lower risk of nephrotoxicity.

Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis.

Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however the optimal dose is unknown. We used the hollow fiber system model of tuberculosis (HFS-TB) to identify 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs) were used to identify doses best able to achieve the HFS-TB-derived target exposures in cavitary tuberculosis and tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI) algorithms to identify the most important predictors of sputum conversion, ADR, and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis treated with a levofloxacin-containing regimen. We also performed probit regression to identify optimal levofloxacin doses in Vietnamese tuberculous meningitis patients. In the HFS-TB, the AUC0-24/MIC associated with maximal Mtb kill was 146, while that associated with suppression of resistance was 360. The most common gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms identified an AUC0-24/MIC of 160 as predictive of microbiologic cure, followed by levofloxacin 2-hour peak concentration and body weight. Probit regression identified an optimal dose of 25 mg/kg as associated with >90% favorable response in adults with pulmonary tuberculosis. The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for replacement of high-dose moxifloxacin in treatment of multidrug-resistant tuberculosis.