ro13-9904 and Liver-Diseases

Ceftriaxone is a third-generation cephalosporin that exhibits saturable plasma protein binding, which influences its pharmacokinetic parameters depending on the dose. Systemic clearance and volume of distribution of total drug show dependence on both concentration and time, whereas for unbound drug these parameters remain constant. The decrease in renal or non-renal clearance with age or in the presence of disease states is often compensated by the concurrent increase in free fraction, resulting in no apparent changes in half-life and no need for dose adjustment. Because of its unusually long plasma half-life, the availability of intramuscular administration and its high intrinsic activity against many organisms, ceftriaxone has become a popular agent in once-daily therapy of infections in paediatric patients, gonococcal infections and outpatient management of pneumonia and osteomyelitis.

Topics: Ceftriaxone; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Kidney Diseases; Liver Diseases; Lyme Disease; Meningitis; Sexually Transmitted Diseases, Bacterial; Tissue Distribution

This article describes the pharmacokinetics of ceftriaxone, a new "third generation" cephalosporin. This antibiotic displays two major characteristics: a very long serum half-life and a good tissue penetration. The properties of ceftriaxone should allow its easy clinical handling.

Topics: Bile; Cefotaxime; Ceftriaxone; Diffusion; Female; Humans; Kidney; Kidney Diseases; Kinetics; Liver; Liver Diseases; Male; Maternal-Fetal Exchange; Pregnancy; Protein Binding; Tissue Distribution

Ceftriaxone is a third-generation cephalosporin that exhibits saturable plasma protein binding, which influences its pharmacokinetic parameters depending on the dose. Systemic clearance and volume of distribution of total drug show dependence on both concentration and time, whereas for unbound drug these parameters remain constant. The decrease in renal or non-renal clearance with age or in the presence of disease states is often compensated by the concurrent increase in free fraction, resulting in no apparent changes in half-life and no need for dose adjustment. Because of its unusually long plasma half-life, the availability of intramuscular administration and its high intrinsic activity against many organisms, ceftriaxone has become a popular agent in once-daily therapy of infections in paediatric patients, gonococcal infections and outpatient management of pneumonia and osteomyelitis.

Topics: Ceftriaxone; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Kidney Diseases; Liver Diseases; Lyme Disease; Meningitis; Sexually Transmitted Diseases, Bacterial; Tissue Distribution

Leptospirosis is one of the leading global zoonotic causes of morbidity and mortality. It is induced by a pathogenic spirochete of the genus Leptospira. The icteric form of leptospirosis is characterized by pronounced hyperbilirubinemia and associated with significantly increased mortality. Conventional static liver function tests insufficiently assess hepatic damage and have limited prognostic value. Dynamic tests, such as indocyanine green plasma (ICG) clearance, more adequately reflect hepatic functional status. In this case report we describe the ICG plasma disappearance rates (ICG-PDR) in a patient with leptospirosis and massive hyperbilirubinemia, expanding our knowledge of liver dysfunction in icteric leptospirosis.. A 21-year-old Caucasian man presented with acute-onset jaundice, myalgia, fever and headaches. Laboratory tests upon admission revealed, most notably, acute kidney failure and hyperbilirubinemia of 17 mg/dl with mild elevation of aminotransferases. In the course of the following 4 days, total serum bilirubin increased to 54 mg/dl. The clinical outcome was favorable with intravenous ceftriaxone and doxycycline. Presumptive diagnosis of leptospirosis was later confirmed by PCR-based amplification of leptospiral DNA in the blood. ICG-PDR values, bilirubin as well as aminotransferases were recorded throughout hospitalization and a 3-month follow-up period. Initially dramatically reduced ICG-PDR (2.0%/min, normal range: 18-25%/min) rapidly normalized within 10 days, while bilirubin remained elevated up to week 7. Mild elevation of serum alanine aminotransferase was at its peak of 124 U/l by day 12 and reached close to normal levels by week 7 upon admission.. Markedly diminished ICG-PDR values presented in this case report suggest severe liver function impairment in the acute phase of icteric leptospirosis. Prolonged elevation of serum bilirubin may not adequately reflect recovery of liver injury in this disease. ICG clearance appears to be a promising marker for the detection of hepatic dysfunction and recovery in icteric leptospirosis in addition to the static tests.

Topics: Alanine Transaminase; Ceftriaxone; Coloring Agents; Doxycycline; Humans; Hyperbilirubinemia; Indocyanine Green; Leptospirosis; Liver Diseases; Liver Function Tests; Male; Young Adult

It has been described a clinical case of late diagnosis of syphilis of the pancreas and liver of elderly patients. Two years before that it was wrongly diagnosed with cancer of the pancreas with liver metastases, and the patient was operated on with the imposition of cholecystostomy. It was conducted appropriate therapy and reconstructive surgery after verification of the diagnosis of syphilis of the pancreas and liver.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Ceftriaxone; Diagnosis, Differential; Diagnostic Errors; Humans; Liver Diseases; Liver Neoplasms; Male; Pancreatic Diseases; Pancreatic Neoplasms; Syphilis; Syphilis Serodiagnosis; Treatment Outcome

The pharmacokinetic profile of ceftriaxone was studied in female healthy goats, induced hepatopathic and nephropathic goats after a single intravenous dose at 50 mg kg(-1). Ceftriaxone persisted for 2 h in plasma of hepatopathic goats compared to 1 h of healthy goats, but the kinetic behaviour followed 'one-compartment open model' in both healthy and hepatopathic goats. Mean value of t((1/2))beta (0.32 +/- 0.008 h) was significantly higher in hepatopathic goats compared to healthy goats (0.19 +/- 0.002 h). Ceftriaxone was recovered at 24 h in urine of hepatopathic goats but it could not be detected in urine of healthy goats. However, its metabolite ceftizoxime was present in urine of healthy goats but not in urine of hepatopathic goats. On the other hand ceftriaxone persisted for 2 h in plasma of kidney damaged goats with significant higher concentration compared to healthy goats but kinetic behaviour followed 'one Compartment open model'. Ceftizoxime was identified with an adequate plasma concentration from 8 h to 12 h post dosing in nephropathic goats. Elimination halflife (t(1/2)beta) of Elimination ceftriaxone (0.38 +/- 0.01 h) in nephropathic goats increased significantly compared to healthy goats (0.19 +/- 0.002 h). Ceftriaxone, not the metabolite ceftizoxime was recovered at 24 h and 48 h post dosing in urine of nephropathic goats, while only ceftizoxime not ceftriaxone was detected in urine of healthy goats.

Topics: Animals; Anti-Bacterial Agents; Carbon Tetrachloride; Ceftriaxone; Female; Goats; Half-Life; Injections, Intravenous; Kidney Diseases; Liver Diseases; Models, Animal; Time Factors; Uranyl Nitrate

Topics: Anti-Bacterial Agents; Biopsy, Needle; Ceftriaxone; Cysts; Diagnosis, Differential; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Abscess; Liver Diseases; Magnetic Resonance Imaging; Male; Middle Aged; Treatment Outcome

Topics: Anti-Bacterial Agents; Blood Component Removal; Ceftazidime; Ceftriaxone; Extracorporeal Circulation; Humans; Liver Diseases; Metabolic Clearance Rate; Ofloxacin; Renal Dialysis; Serum Albumin; Teicoplanin

Forty patients with spontaneous bacterial peritonitis, three of whom had complicating acute hepatitis syndrome, eight late-onset hepatic failure, and 29 with cirrhosis, were treated with ceftriaxone 2 g intravenously once daily for 5 days. Ascitic fluid culture was positive in 28 patients, with Escherichia coli and Klebsiella as common isolates. All the bacteria isolated were sensitive to ceftriaxone except Enterococcus faecalis, which was isolated in a cirrhotic patient. All culture-positive patients sensitive to ceftriaxone showed bacteriological cure and 26 (65%) patients showed cytological cure after 48 hours of treatment. A total of 95% were cured of their infection after 5 days of treatment. Twelve (30%) patients died during hospitalisation after documented cure of their spontaneous bacterial peritonitis (renal failure, gastrointestinal bleed and cerebral oedema were the primary causes of death). Infection-related mortality due to Pseudomonas septicaemia was seen in one cirrhotic patient.

Topics: Adolescent; Adult; Ceftriaxone; Cephalosporins; Escherichia coli Infections; Female; Humans; Klebsiella Infections; Liver Diseases; Male; Middle Aged; Peritonitis; Prospective Studies

We studied the intrahepatic diffusion of ceftriaxone, a new third generation, very potent cephalosporin with a long serum half-life. Sixteen patients had percutaneous liver biopsy for suspected liver disease or protracted fever of unknown origin. Serum samples and liver biopsy specimens were taken simultaneously. Serial determinations of ceftriaxone concentrations showed that the hepatic half-life was significantly shorter than the serum half-life. We suggest that ceftriaxone be used in higher or more closely spaced doses for the treatment of liver infections.

Topics: Adult; Aged; Ceftriaxone; Female; Half-Life; Humans; Liver; Liver Diseases; Male; Middle Aged

Topics: Adolescent; Adult; Aged; Ceftriaxone; Female; Humans; Kinetics; Liver; Liver Diseases; Male; Middle Aged

The pharmacokinetics of cefotaxime, its desacetyl metabolite and ceftriaxone were studied in 72 patients with various degrees of renal and hepatic failure. Patients with severe renal failure (creatinine clearance 3 to 10 ml/min) had a cefotaxime serum half-life of 2.6 h, a desacetyl cefotaxime serum half-life of 10 h and ceftriaxone serum half-life of 17 h. In the case of ceftriaxone, this serum half-life could be very variable--increasing to over 50 h, possibly due to co-existing hepatic dysfunction. Increases in serum half-life were found for cefotaxime in the presence of liver disease.

Topics: Adult; Aged; Cefotaxime; Ceftriaxone; Female; Half-Life; Humans; Kidney Diseases; Kinetics; Liver Diseases; Male; Middle Aged

The disposition profile of ceftriaxone was studied in eight normal subjects and in 15 subjects with various degrees of chronic liver damage (alcoholic fatty liver [FL] and cirrhosis without [C] and with [CA] ascites) who received bolus injections of ceftriaxone, 1 gm iv. Plasma protein binding fell in all. As a result, mean free fraction in plasma rose between 140% (FL) and 320% (CA). An exceptionally large rise (1270%) occurred in one subject with CA when the condition was aggravated by renal impairment. Fourteen of 15 subjects had renal clearance of unbound drug of the same order as that in healthy adults. In chronic liver disease, mean nonrenal clearance of unbound drug fell with severity of liver damage. Kinetic parameters with reference to total drug differed in normal subjects and subjects with CA. Kinetic changes in the latter were such that elimination t 1/2 beta did not differ (9.7 and 8.4 hr). Because of the wide therapeutic range of ceftriaxone, subjects with chronic liver disease would require no dose adjustments, whereas dose reductions are envisaged for subjects with cirrhosis (C,CA) on the basis of increased unbound drug concentrations.

Topics: Adult; Cefotaxime; Ceftriaxone; Chromatography, High Pressure Liquid; Female; Humans; Injections, Intravenous; Kidney; Kinetics; Liver Diseases; Liver Function Tests; Male; Middle Aged; Protein Binding; Serum Albumin

In patients with normal hepatic and renal function, between 30 and 60 percent of administered ceftriaxone is eliminated by nonrenal (biliary) mechanisms. Substantial nonrenal elimination reduces the need for dose adjustments in mild and moderate renal impairment. Minor increases in the biologic half-life (12 hours versus normal of 8 hours) of ceftriaxone have been seen in (functionally) anephric patients with normal extrarenal clearance mechanisms. Anephric patients with decreased nonrenal elimination (additional liver damage) showed a greater increase in biologic half-lives (greater than 15 hours). In patients with various degrees of liver insufficiency (alcoholic fatty liver and cirrhosis with and without ascites), only those with ascites showed significant changes in total drug clearance and volume of distribution. However, these changes in patients with ascites were such that they did not demonstrate significantly different biologic half-lives (9.7 hours versus normal of 8 hours). Simulations of observed concentration versus time data support a physiologic disposition model whereby ceftriaxone, like other cephalosporins, distributes only in plasma and in the extravascular-extracellular (interstitial) fluid and ceftriaxone is saturably bound to albumin in both spaces. All observations in normal subjects and patients were in good agreement with the physiologic disposition model predictions. The consequences of the nonlinear binding behavior of ceftriaxone are such that they favor the administration of ceftriaxone in a large single dose rather than in divided doses. No major drug accumulation is expected in patients with renal or hepatic insufficiency, but anephric patients with a decrease of more than 80 percent in nonrenal elimination will require dose adjustments.

Topics: Blister; Blood Proteins; Cefotaxime; Ceftriaxone; Humans; Kidney Diseases; Kinetics; Liver Diseases; Models, Biological; Protein Binding

The pharmacokinetic behavior of ceftriaxone was studied in 60 patients with severe community- or hospital-acquired infections. Serum concentrations one to three hours after a 30-minute intravenous infusion appeared to be dose related. The mean two-hour levels were 110, 138, and 146 mg/liter, and trough values averaged 54.9, 28.5, and 16.1 mg/liter after doses of 1.0, 2.0, and 3.0 g, respectively. At 24 hours, values were at least 10 mg/liter in all but seven patients. The serum half-life of ceftriaxone in all patients and for all dosage regimens varied from 3.5 to 59.4 hours. In patients with normal renal function (serum creatinine 1.30 mg/dl or less) the mean half-life was 8.2 hours. In patients with moderate (creatinine 1.34 to 1.83 mg/dl) and severe (creatinine 2.40 mg/dl or greater) renal insufficiency, the mean serum half-lives were 12.8 and 12.4 hours, respectively. In six patients who had severe renal failure and concomitant hepatic dysfunction, half-lives ranged from 23.7 to 59.4 hours. Single daily doses of 2.0 g of ceftriaxone produced adequate serum concentrations. Dose reductions are recommended in patients with both renal and hepatic dysfunction.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Half-Life; Humans; Kidney Diseases; Kinetics; Liver Diseases; Middle Aged