Levofloxacin Pharmacokinetics and Pharmacodynamics in Patients with Severe Burn Injury

ABSTRACT Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ± standard deviations; age, 41 ± 17 years; weight, 81 ± 12 kg; creatinine clearance, 114 ± 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ± 3.2 liters/h, 7.8 ± 1.6 h, and 93 ± 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of ≤0.5 μg/ml and MICs of ≤1 μg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 μg/ml or any organism with a MIC of ≥2 μg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 μg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.

Download Full-text

Experimental evidence for a significant impairment of host defense for gram-negative organisms by a specific cutaneous toxin produced by severe burn injuries

Journal of Trauma and Acute Care Surgery ◽

10.1097/00005373-197605000-00025 ◽

1976 ◽

Vol 16 (5) ◽

pp. 420

Author(s):

G. A. Schoenberger ◽

David C. Colletti ◽

DAVID B. PILCHER

Keyword(s):

Experimental Evidence ◽

Host Defense ◽

Burn Injuries ◽

Severe Burn ◽

Gram Negative ◽

Significant Impairment ◽

Severe Burn Injuries ◽

Gram Negative Organisms

Download Full-text

The rise of factor X level in blood plasma of patients at severe burn injuries

Journal of Burn Care & Research ◽

10.1093/jbcr/irab235 ◽

2021 ◽

Author(s):

George P Kozynets ◽

Volodymyr P Tsyhankov ◽

Daria S Korolova ◽

Olga V Gornytska ◽

Olexiy M Savchuk ◽

...

Keyword(s):

Protein C ◽

Antithrombin Iii ◽

Burn Injury ◽

Activated Partial Thromboplastin Time ◽

Burn Injuries ◽

Factor X ◽

Severe Burn ◽

Clotting Factors ◽

Thrombotic Complications ◽

Severe Burn Injuries

Abstract This work is dedicated to the detection of imbalance between the pro- and anti-coagulant branches of hemostasis at severe burn injuries by evaluating the content or activity of individual clotting factors. To select the targets for accurate diagnostics we measured the concentrations of soluble fibrin monomeric complexes and fibrinogen, levels of total prothrombin, factor X, protein C and antithrombin III, and recorded the time of clotting in activated partial thromboplastin time and prothrombin time tests. Factor X level was increased in 26 % of patients on the first day after the burn and it rose further in 62 % patients on the 14 th day of recovery. Increasing factor X level is assumed to be a risk factor of thrombotic complications. We propose to use it as a marker of predisposition to thrombosis at severe burn injury.

Download Full-text

Тhe use of corticosteroids in patients with severe burn injuries

Actual problems of modern medicine ◽

10.26565/2617-409x-2020-5-07 ◽

2020 ◽

Keyword(s):

Burn Injury ◽

Burn Shock ◽

Burn Patients ◽

Severe Burn ◽

Septic Complications ◽

Results Of Treatment ◽

Adults And Children ◽

Severe Burn Injuries ◽

Burn Disease ◽

Severe Burn Injury

Modern treatment of burns has led to a significant reduction in mortality in patients with burns whose injuries were fatal several years ago. However, along with improved survival, new problems arose in the treatment of burn patients. Systemic inflammatory response, capillary leak, sepsis top the list of the most common problems in both adults and children with severe thermal injury. Currently, new strategies are being developed and studied in the treatment of this category of patients. One of the ways to improve the results of treatment of patients with severe burn injury is to prescribe corticosteroids, both in the stage of burn shock and in the development of septic complications. Do corticosteroids reduce mortality and improve recovery in burn patients? The discussion about this has been going on for many years, but the opinion about their effectiveness remains controversial. An analysis of the literature shows that corticosteroids can play a significant role in the treatment of patients with severe burn injury and can be successfully used at any stage of a burn disease. The effect of reducing capillary leakage, increasing myocardial contractility, antiemetic, membrane-stabilizing effect of corticosteroids will be useful in the stage of burn shock. The anti-inflammatory, immunomodulatory effect of corticosteroids will play a role in any stage of a burn disease. With the aim of preventing and treating sepsis, corticosteroids may be useful in the stage of toxemia, septicotoxemia. It is also necessary to remember about adrenal insufficiency, which develops in burn patients. The article analyzes the literature, substantiates the use of corticosteroids in patients with severe burn injury in different periods of a burn disease.

Download Full-text

Pharmacokinetics of thiamphenicol in normal and pasteurella multocida infected lactating goats

International Journal of Pharmacology and Toxicology ◽

10.14419/ijpt.v5i2.7598 ◽

2017 ◽

Vol 5 (2) ◽

pp. 61

Author(s):

Mossad Elsayed ◽

Ashraf Elkomy ◽

Faten Ibrahim

Keyword(s):

Intravenous Injection ◽

Pasteurella Multocida ◽

The Body ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Once Daily ◽

Intramuscular Dose ◽

Lactating Goats ◽

Urine Concentrations ◽

Repeated Administrations

The pharmacokinetic parameters of thiamphenicol following intravenous and intramuscular (single & repeated) administrations were estimated in normal and experimentally pasteurella multocida infected goats. Following a single intravenous injection of 30 mg thiamphenicol /kg b.wt. in normal goats, thiamphenicol could be detected therapeutically for 24 hours post intravenous injection. The serum concentration – time curve of thiamphenicol following intravenous injection showed that the drug obeyed a two compartments open model. The intramuscular bioavailability of thiamphenicol in normal goats was 66.63 %. Intramuscular injection of 30 mg thiamphenicol per kilogram body weight once daily for five consecutive days in normal and pastreulla multocida infected goats revealed a lower significant serum thiamphenicol concentration in pastreulla multocida infected goats compared with normal goats, also it’s found that: marked significant decrease in ( k1, K12, K21, T0.5(α) , T0.5(β), Tmax and CLtot in normal compared with infected goats, on the other hand a significant increase in Cmax,AUC, C0,B and β in normal compared with infected goats. Thiamphenicol was cleared by all clearance processes (Cltot) in the body at significant faster rates in Pasteurella multocida infected goats than in normal goats. The concentrations of thiamphenicol in milk were significantly lower in Pasteurella multocida infected goats than in normal goats. The mean peak urine concentrations of thiamphenicol were reached 4 hours after each intramuscular dose with a lower significant concentration in Pasteurella multocida infected goats than in normal goats.

Download Full-text

Efficacy and Safety of High Vs Standard Daptomycin Doses Examined in Chinese Patients With Severe Burn Injuries by Pharmacokinetic Evaluation

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa020 ◽

2020 ◽

Vol 41 (3) ◽

pp. 705-713

Author(s):

Yingzi Huang ◽

Guozhong Lv ◽

Linlin Hu ◽

Yunfu Wu ◽

Nan Guo ◽

...

Keyword(s):

Mass Spectrometry ◽

Burn Injury ◽

Standard Dose ◽

Burn Injuries ◽

Chinese Patients ◽

High Dose ◽

Severe Burn ◽

Serious Adverse Events ◽

Severe Burn Injuries ◽

High Doses

Abstract Previous studies and the concentration-dependent antibacterial actions of daptomycin suggested that a high dose would be needed for difficult-to-treat infections in burn patients. Here, we evaluated the effects of administration of low and high doses of daptomycin in patients with severe burn injuries. The study retrospectively analyzed 10 patients with severe burn injuries, using pharmacokinetic (PK) and pharmacodynamic (PD) evaluations of daptomycin doses given to combat serious infections. Daptomycin was administered as a single dose or by multiple doses intravenously at a standard dose of 6 mg/kg/d or a high dose of 12 mg/kg/d for 7 to 14 days. The serum concentrations of daptomycin from patients were analyzed by liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS). Burn injury patients treated with high-dose daptomycin had a linear PK profile and a negative correlation between the AUC0–24 and Baux score (R2 = .953 and R2 = .801). The Cmax, AUC0–24, and t(h)½ increased significantly compared with patients given a standard dose. The efficacy of daptomycin against Staphylococcus aureus showed significantly higher rates of (AUC0–24)/MIC and Cmax/MIC after high-dose daptomycin compared with the standard dose, reflected in a significant correlation between a high dose and the Baux score (r = .976, P < .001). Positive S. aureus cultures from two of three high-dose and none of two daptomycin low-dose patients converted from positive to negative after therapy. No serious adverse events or discontinuation of the drug occurred during the treatment period. Daptomycin doses up to 12 mg/kg/d were well tolerated in Chinese patients with severe burn injuries, which were complicated by infections with S. aureus.

Download Full-text

Steady-State Pharmacokinetics of Abacavir in Plasma and Intracellular Carbovir Triphosphate following Administration of Abacavir at 600 Milligrams Once Daily and 300 Milligrams Twice Daily in Human Immunodeficiency Virus-Infected Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01000-08 ◽

2009 ◽

Vol 53 (4) ◽

pp. 1532-1538 ◽

Cited By ~ 32

Author(s):

Graeme Moyle ◽

Marta Boffito ◽

Carl Fletcher ◽

Chris Higgs ◽

Phillip E. Hay ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

High Performance ◽

Pharmacokinetic Parameters ◽

Virologic Suppression ◽

Open Label ◽

Time Curve ◽

Mixed Effect ◽

Once Daily ◽

Immunodeficiency Virus ◽

And Gender

ABSTRACT Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days −1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC0-24) and comparable CBV-TP concentrations at the end of the dosing interval (C τ). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C max) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC0-24 and 99% higher CBV-TP C max than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC0-24 and 81% higher weight-adjusted CBV-TP AUC0-24 than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C τ values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

Download Full-text

Pharmacokinetics of Rifampin and Clarithromycin in Patients Treated for Mycobacterium ulcerans Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00099-10 ◽

2010 ◽

Vol 54 (9) ◽

pp. 3878-3883 ◽

Cited By ~ 34

Author(s):

J. W. C. Alffenaar ◽

W. A. Nienhuis ◽

F. de Velde ◽

A. T. Zuur ◽

A. M. A. Wessels ◽

...

Keyword(s):

Extended Release ◽

Controlled Trial ◽

Mycobacterium Ulcerans ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Release Formulation ◽

Once Daily ◽

Extended Release Formulation ◽

Liquid Chromatography Tandem Mass ◽

Tandem Mass Spectroscopy

ABSTRACT In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Pharmacokinetic parameters were calculated with the MW/Pharm (version 3.60) program. Comedication with CLA resulted in a 60% statistically nonsignificant increase in the area under the plasma concentration-time curve (AUC) for RIF of 25.8 mg·h/liter (interquartile ratio [IQR], 21.7 to 31.5 mg·h/liter), whereas the AUC of RIF was 15.2 mg·h/liter (IQR, 15.0 to 17.5 mg·h/liter) in patients comedicated with SM (P = 0.09). The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg·h/liter (IQR, 1.5 to 3.8 mg·h/liter) and 8.0 mg·h/liter (IQR, 6.7 to 8.6 mg·h/liter), respectively. The median concentration of CLA was above the MIC of M. ulcerans, but that of 14OH-CLA was not. In further clinical studies, a dose of CLA of 7.5 mg/kg twice daily should be used (or with an extended-release formulation, 15 mg/kg should be used) to ensure higher levels of exposure to CLA and an increase in the time above the MIC compared to those achieved with the currently used dose of 7.5 mg/kg once daily.

Download Full-text

Effect of pharmacokinetic/pharmacodynamic ratio on tigecycline clinical response and toxicity in critically ill patients with multidrug-resistant Gram-negative infections

SAGE Open Medicine ◽

10.1177/2050312120958897 ◽

2020 ◽

Vol 8 ◽

pp. 205031212095889

Author(s):

Jesus Ruiz ◽

Paula Ramirez ◽

Esther Villarreal ◽

Mónica Gordon ◽

María Ángeles Sánchez ◽

...

Keyword(s):

Clinical Response ◽

Critically Ill ◽

Critically Ill Patients ◽

Total Bilirubin Level ◽

Optimal Dose ◽

Multidrug Resistant ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Free Concentration ◽

Gram Negative

Introduction: The information about the pharmacokinetics and optimal dose of tigecycline in critically ill patients with severe underlying diseases is limited and controversial. In this study, we evaluate the pharmacokinetic parameters of tigecycline in critically ill patients with multidrug-resistant Gram-negative infection and explore the association between the pharmacokinetic/pharmacodynamic ratio and treatment response. Methods: A prospective study was designed including critically ill patients treated with tigecycline for multidrug-resistant Gram-negative infections. Blood samples were collected at day 3–5 of treatment, and pharmacokinetics parameters were evaluated using NONMEM® software. Relationship between area under the free concentration–time curve and minimum inhibitory concentration ratio (fAUC/MIC) and treatment failure was evaluated. Association between tigecycline fAUC and hepatobiliary toxicity was also investigated. Results: Twenty-five critically ill patients were included in the study. In the pharmacokinetic model, weight and total bilirubin level were found to be significant predictors of tigecycline clearance. Fifteen (60.0%) patients achieved an fAUC/MIC ratio >4.5, seven (28.0%) an fAUC/MIC > 6.96 and only three (12.0%) an fAUC/MIC > 17.9. No differences in fAUC/MIC ratio were obtained between those patients with and without clinical failure (5.28 (IC95%: 2.57–7.94) vs 8.71 (3.57–13.84)). fAUC values were higher in those patients who suffered hepatobiliary disorders (7.63 (3.93–11.34) vs 17.63 (7.85–26.28) mg/L/h). Conclusion: An important percentage of critically ill patients with multidrug-resistant Gram-negative infection treated with tigecycline do not achieve an appropriate pharmacokinetic/pharmacodynamic value. Tigecycline fAUC seems to be associated with hepatobiliary disorders in this study population. The effect of fAUC/MIC ratio on clinical response remains unclear.

Download Full-text

Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.9.2359 ◽

1998 ◽

Vol 42 (9) ◽

pp. 2359-2364 ◽

Cited By ~ 6

Author(s):

Martina Kinzig-Schippers ◽

Uwe Fuhr ◽

Marina Cesana ◽

Carola Müller ◽

A. Horst Staib ◽

...

Keyword(s):

Steady State ◽

Adverse Events ◽

Compartment Model ◽

Volume Of Distribution ◽

Reversed Phase ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Elimination Phase ◽

Once Daily ◽

Model Independent

ABSTRACT Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1.02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.

Download Full-text