ru-66647 and Chemical-and-Drug-Induced-Liver-Injury

A case of mild hepatocellular injury associated with the administration of telithromycin in a patient with no risk factors for hepatotoxicity is presented.. A 44-year-old man with no significant past medical history arrived at the emergency room after six days of high fever, chills, headache, neck stiffness, and back pain. Five days earlier, he visited a family medicine clinic for his symptoms and oral telithromycin 800 mg daily was prescribed for a suspected upper-respiratory-tract infection. The patient stopped taking the drug after three days due to persistent symptoms. On admission, the patient's laboratory tests revealed an aspartate transaminase (AST) concentration of 68 units/L, an alanine transaminase (ALT) value of 155 units/L, and an erythrocyte sedimentation rate of 40 mm/hr. The patient was not taking any long-term medications, had taken only aspirin for his fever, and denied the use of alcohol and illegal drugs. The patient was admitted to the general medical unit with a diagnosis of possible viral hepatitis. His urine culture was negative, and serology tests later revealed no evidence of hepatitis A, B, or C. Ibuprofen, pantoprazole, and enoxaparin were prescribed. On hospital day 2, the patient's AST and ALT concentrations had decreased to 50 and 110 units/L, respectively. By day 3, the patient's symptoms had improved and he remained afebrile. His AST and ALT values had further decreased to 41 and 105 units/L, respectively. He was then diagnosed with acute viral upper-respiratory-tract infection with mild hepatotoxicity associated with telithromycin and was discharged home with orders for follow-up at the family medicine clinic.. A patient without risk factors for hepatotoxicity developed mild elevations in hepatic transaminases after receiving telithromycin for the treatment of a suspected upper-respiratory-tract infection.

Topics: Acute Disease; Adult; Alanine Transaminase; Anti-Bacterial Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Humans; Ketolides; Liver; Male; Respiratory Tract Infections

Telithromycin is a ketolide antibiotic approved by the U.S. Food and Drug Administration for acute bacterial infections causing sinusitis, bronchitis, and community-acquired pneumonia.. To describe 3 cases of severe hepatotoxicity in patients receiving telithromycin.. Case reports.. A tertiary care medical center.. 3 previously healthy patients who had recently taken telithromycin and took no other prescription medications.. Serologic, histologic, and liver function tests.. Within a few days of receiving telithromycin, the patients presented with acute hepatitis. All had jaundice and markedly abnormal results on liver function tests. Results of viral serologic tests were negative. One patient spontaneously recovered, 1 required orthotopic liver transplantation, and 1 died. Histologic examination in the latter 2 patients showed massive hepatic necrosis.. Two patients had some history of alcohol use. The frequency of severe telithromycin-related hepatotoxicity cannot be established with case reports.. Telithromycin can cause severe hepatotoxicity. Caution is advised in prescribing this drug pending additional postmarketing surveillance data.

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Humans; Ketolides; Liver; Male; Middle Aged; Protein Synthesis Inhibitors

Macrolides, ketolides and streptogramins are three families of antibiotics with different chemical structures, sharing the same mechanism of action. All three bind to distinct bases of the peptidyl transferase center of ARNr 23S. Their antibacterial spectrum practically overlaps, but dissimilarities in affinity and/or number of binding sites determine differences in the intensity of their antibacterial effects (bacteriostatic or bactericidae) and in their activity against strains with acquired resistance mechanisms. These agents are active against the majority of gram-positive microorganisms and many intracellular microorganisms for growth. Over the last five years in our country, the percentage of macrolide-resistant pneumococci and S. pyogenes strains has increased substantially. Telithromycin (ketolide) and Synercid (streptogramin) have shown maintained activity against these strains. Macrolides, ketolides and streptogramins are metabolized in the liver through CYP 3A4 and they can partially block the activity of the enzyme, interfering with the metabolism of other drugs that use the same metabolic pathway. There is little elimination through the urine, with the exception of clarithromycin. High concentrations are reached in the cellular cytoplasm, but they do not diffuse to the CSF. These agents are included among class B drugs for use during pregnancy. Tolerance to macrolides and telithromycin is good and they have few associated adverse effects. The main clinical indication for these drugs is in empirical treatment of mild to moderate, community-acquired, upper and lower respiratory tract infections. Synercid is indicated in the treatment of infections due to methicillin-resistant staphylococci and glycopeptide-resistant enterococci.

Topics: Anti-Bacterial Agents; Biotransformation; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Resistance; Gastrointestinal Diseases; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hearing Loss, Sensorineural; Humans; Ketolides; Macrolides; Microsomes, Liver; Protein Synthesis Inhibitors; RNA, Bacterial; RNA, Ribosomal, 23S; Streptogramins

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.

Topics: Adverse Drug Reaction Reporting Systems; Aripiprazole; Chemical and Drug Induced Liver Injury; Data Mining; Databases, Factual; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Exenatide; Humans; Hypercalcemia; Ketolides; Pancreatitis; Peptides; Rhabdomyolysis; Rosuvastatin Calcium; Suicide; Teriparatide; Time Factors; United States; United States Food and Drug Administration; Varenicline; Venoms

Idiosyncratic drug-induced hepatotoxicity accounts for about 13% of all cases of acute liver failure, therefore cited as the most frequent reason for post-marketing drug withdrawal. Despite this, the underlying mechanisms remain poorly understood due to lack in adequate screening assays and predictive in vitro models. Hepatic transporters play a crucial role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition, including toxicity and loss of efficacy. Inflammation is one condition for demonstrated variable drug response, attributed in part, to changes in function of drug transporters. The present study investigates the implication of two important hepatic transporters (MDR1 and MRP2) in idiosyncratic drug-induced hepatotoxicity in the presence and absence of an inflammatory context. The synergistic effect of idiosyncratic drugs (Trovafloxacin, nimesulide, telithromycin, and nefazodone) and inflammatory stimuli (TNF-α + LPS) on the efflux activity of hepatic transporters was studied using microvolume cytometry. Our results demonstrated on the one hand that both MDR1 and MRP2 are variably implicated in idiosyncratic drug-induced liver injury and on the other hand that the occurrence of an inflammatory reaction during idiosyncratic drug therapy can noticeably modulate this implication. In the absence of an inflammatory stress, none of the four tested drugs modulated the efflux activity of MRP2; nevertheless telithromycin and nefazodone inhibited the efflux activity of MDR1. Upon occurrence of an inflammatory stress, the inhibitory potential of trovafloxacin, nimesulide, and nefazodone on the efflux activity of MRP2 was noticeably revealed, while the telithromycin and nefazodone-induced inhibition of MDR1 was clearly attenuated. Knowledge of underlying mechanisms may significantly contribute to elimination of potential hepatotoxic drugs long before marketing and to prevention of drug-induced hepatotoxicity.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Sub-Family B Member 4; Biological Transport; Chemical and Drug Induced Liver Injury; Flow Cytometry; Fluoroquinolones; Gene Expression Regulation; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Ketolides; Lipopolysaccharides; Liver; Naphthyridines; Piperazines; Sulfonamides; Triazoles; Tumor Necrosis Factor-alpha; Xenobiotics

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): -0.4, 0.1) and -2.2 diabetes cases per 1,000 person-years (95% CI: -6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: -0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Chemical and Drug Induced Liver Injury; Diabetes Mellitus; Drug Monitoring; Electronic Data Processing; Electronic Health Records; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ketolides; Male; Outcome Assessment, Health Care; Product Surveillance, Postmarketing; Retrospective Studies; Rhabdomyolysis

Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions.. Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ascites; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Humans; Jaundice; Ketolides; Liver Failure; Male; Middle Aged; Pleural Effusion

With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin.. To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs).. Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin.. A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS.. A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.

Topics: Adverse Drug Reaction Reporting Systems; Algorithms; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Data Interpretation, Statistical; Humans; Ketolides; Liver Diseases; Odds Ratio; Poisson Distribution; United States; United States Food and Drug Administration

Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Bronchitis, Chronic; Chemical and Drug Induced Liver Injury; Drug Approval; Humans; Ketolides; Risk Assessment; Sinusitis; United States; United States Food and Drug Administration

Topics: Advisory Committees; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Approval; Humans; Ketolides; Liver Failure, Acute; Patient Selection; Scientific Misconduct; United States; United States Food and Drug Administration

Topics: Advisory Committees; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Approval; Humans; Ketolides; Product Surveillance, Postmarketing; Scientific Misconduct; United States; United States Food and Drug Administration

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Community-Acquired Infections; Drug Labeling; Humans; Insurance Claim Reporting; Ketolides; Liver Failure; Patient Care Team; Pneumonia, Bacterial; United States; United States Food and Drug Administration

Recent reports have described cases of telithromycin-related hepatotoxicity. The objective of this study is to quantify the effect of telithromycin use on the risk of hepatotoxicity.. We conducted a spontaneous-report case-control study of hepatotoxicity in telithromycin recipients using reports from the US FDA Adverse Event Reporting System. Reports from between 1 January 2005 and 30 June 2005 were examined. Cases included reports of patients with abnormal liver function tests, hepatocellular damage and hepatic impairment, while patients with reported conditions with similar reporting probabilities were considered as controls. The primary outcome measure of the analysis was the reporting odds ratio (ROR) evaluating the a priori hypothesis that telithromycin use confers an elevated risk of hepatotoxicity relative to other agents.. A total of 2219 cases and 20,667 controls were identified. We estimated an ROR for hepatotoxicity associated with telithromycin compared with other agents of 1.82 (95% CI 1.12, 2.96) after controlling for age and gender, approximating an 82% excess risk in users of telithromycin relative to users of other agents.. This analysis is the first to specifically quantify the effect of telithromycin on the risk of hepatotoxicity. Telithromycin use may increase the risk of hepatotoxicity by >80%. Biases inherent in spontaneous reports include under-reporting of events and differential or time-varying reporting due to enhanced clinician awareness. Future studies should employ alternative data sources because of the inherent limitations of passive surveillance systems.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anti-Bacterial Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Humans; Ketolides; Liver Diseases; Male; Middle Aged; Odds Ratio; United States

Antibiotic-associated hepatotoxicity is rare. With widespread use of antimicrobial agents, however, hepatic injury occurs frequently, and among adverse drug reactions, idiosyncratic reactions are the most serious.. A 25-year-old male patient, with a height of 175 cm and weight of 72 kg presented to Marmara University Hospital Emergency Department, Istanbul, Turkey, with 5 days' history of jaundice, malaise, nausea, and vomiting. He had been prescribed telithromycin 400 mg/d PO to treat an upper respiratory tract infection 7 days prior. Admission laboratory tests were as follows: alanine aminotransferase, 67 U/L (reference range, 10-37 U/L); aspartate aminotransferase, 98 U/L (10-40 U/L); alkaline phosphatase, 513 U/L (0-270 U/L); gamma-glutamyltransferase, 32 U/L (7-49 U/L); amylase, 46 U/L (0-220 U/L); total bilirubin, 20.1 mg/dL (0.2-1.0 mg/dL); direct bilirubin, 14.8 mg/dL (0-0.3 mg/dL); and albumin, 4.7 mg/dL (3.5-5.4 mg/dL). No toxin, alcohol, or other drugs were reported. The patient had suffered a previous episode of "acute hepatitis of unknown origin," that occurred after telithromycin usage. Both incidents occurred within a year.. Telithromycin is the first of the ketolide antibacterials to receive US Food and Drug Administration approval for clinical use. It has been associated with infrequent and usually reversible severe hepatic dysfunction. Based on a score of 8 on the Naranjo adverse drug reaction probability scale, telithromycin was the probable cause of acute hepatitis in this patient, and pathological findings suggested drug-induced toxic hepatitis. Recurrence of hepatitis attack might have been avoided if the initial incident had been communicated to the attending physician who prescribed telithromycin the second time.. Here we report a case of acute hepatitis probably associated with the administration of telithromycin.

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Ketolides; Male; Respiratory Tract Infections

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Humans; Ketolides; Liver; Male; Middle Aged; Protein Synthesis Inhibitors

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Ketolides; Protein Synthesis Inhibitors

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Ketolides; Protein Synthesis Inhibitors