amoxicillin-potassium-clavulanate-combination and Chemical-and-Drug-Induced-Liver-Injury

Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Topics: Amoxicillin-Potassium Clavulanate Combination; Bile Acids and Salts; Bile Ducts; Biomarkers; Biotransformation; Carbamazepine; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Epithelial Cells; Humans; Liver

Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug-induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Chemical and Drug Induced Liver Injury; Floxacillin; Humans; Isoniazid; Pharmaceutical Preparations

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

Topics: Alleles; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Azetidines; Benzylamines; Carbamazepine; Chemical and Drug Induced Liver Injury; Diclofenac; Dideoxynucleosides; Drug Hypersensitivity; Floxacillin; Genetic Markers; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-DQ alpha-Chains; Humans; Lapatinib; Pharmacogenetics; Quinazolines; Skin; Stevens-Johnson Syndrome; Ticlopidine

Drug-induced liver injury (DILI) remains an important disease in clinical practice. It is difficult to predict, diagnose and manage. Studies in the peer-reviewed literature in the last 2 years, focusing on the diagnosis, prediction and management of DILI will be reviewed.. Antibiotics remain the most common drug causing DILI in the United States and Europe. Expert opinion may still be the better method of diagnosing DILI compared with an objective tool such as the Roussel-Uclaf Causality Assessment Method. Hepatitis E represents an alternative diagnosis to some cases of presumed drug hepatotoxicity. There is ongoing research into the genetics of the pathophysiology and susceptibility of DILI. A genome-wide association study confirmed the association between human leukocyte antigen (HLA) class II and susceptibility to coamoxiclav (amoxicillin-clavulanic acid) induced DILI. There is new information on the protective effect of HLA-DRB1*07 family of alleles. MicroRNAs are a potential marker of DILI. Keratin variants may predict outcome of acute liver failure. N-acetylcysteine may be protective against DILI while taking antituberculosis medication.. Recent findings in the genetics of pathophysiology and susceptibility of DILI can help with predicting and avoiding DILI in clinical practice and provide the foundation for ongoing research.

Topics: Acetylcysteine; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Disease Susceptibility; Europe; Female; Genome-Wide Association Study; Genotype; HLA-DRB1 Chains; Humans; Male; Protective Agents; Risk Factors; United States

Drug-induced liver injury (DILI) is a rare but potentially serious idiosyncratic reaction. By using candidate gene and genome-wide association studies, replicated associations for DILI susceptibility with HLA genes and genes relevant to drug metabolism have been detected, mainly since 2000. The HLA associations include a strong association between flucloxacillin-induced injury and the class I allele B*5701 and weaker associations for co-amoxiclav and ximelagatran DILI with the class II genotype. These associations suggest an injury mechanism involving an immune response, possibly to a complex of drug or metabolite and protein. For genes relevant to drug metabolism, the best replicated association is between isoniazid DILI and NAT2 slow acetylation. Homozygosity for GSTM1 null and/or GSTT1 null alleles also seems to be a risk factor for DILI, with associations described independently for several drugs. Other not-yet-replicated associations have been described for genes relevant to drug metabolism and oxidative stress and cytokine genes.

Topics: Alleles; Amoxicillin-Potassium Clavulanate Combination; Arylamine N-Acetyltransferase; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Forecasting; Genome-Wide Association Study; Genotype; Glutathione Transferase; Humans; Isoniazid; Risk Factors

The field of drug-induced liver injury (DILI) continues to expand in terms of global registries and with new agents added every year. Given the need to improve on our current methods of preclinical testing and monitoring for DILI during both clinical trials and in the post-approval setting, there is increasing research aimed at better understanding why injury occurs and who is most susceptible. To this end, the active pursuit of biomarkers that will predict injury prior to its occurrence and genetic testing that can identify individuals at risk of DILI continue to be at the forefront.. While alanine aminotransferase (ALT) testing remains the workhorse of biochemical monitoring, it only detects hepatic injury after it has occurred and, therefore, is not a true predictor. The utility and shortcomings of ALT and other liver tests are reviewed along with a synopsis of several other candidate biomarkers that are being studied. In addition, we review the recent data supporting testing for genetic predisposition to DILI and how identifying clinical risk factors may translate into better means for preventing DILI.. We update the basis on which age and gender are considered risk factors for DILI, and review the latest reports detailing the association of several candidate genes and the development of DILI in a susceptible patient. Human leukocyte antigen-B*5701 is closely linked to the hypersensitivity reaction seen with abacavir, and such screening has been successfully incorporated into HIV treatment around the globe and offers the promise that testing for other genetic markers will soon become a routine part of clinical practice. At present, candidate genes conferring specific susceptibility to DILI have been identified for a relatively few agents (e.g., flucloxacillin, amoxicillin-clavulanate, ximelagatran and isoniazid), but many more are under study. Preventing DILI often comes down to avoiding the use of potentially hepatotoxic drugs in certain situations, and we review the clinical scenarios in which this is most relevant.. Given the number and range of studies aimed at identifying predictors of DILI, the focus of this review is to summarize what we consider to be the most relevant new information published on the topics of clinical and genetic factors that predispose to DILI, the use of biomarkers as predictors of acute DILI, along with advances in prevention strategies.

Topics: Acetaminophen; Adult; Aged; Aging; Alanine Transaminase; Amoxicillin-Potassium Clavulanate Combination; Analgesics, Non-Narcotic; Anti-Bacterial Agents; Antitubercular Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Predisposition to Disease; Humans; Isoniazid; Male; Middle Aged; Pharmaceutical Preparations; Risk Factors

Topics: Amoxicillin-Potassium Clavulanate Combination; Antitubercular Agents; Azathioprine; Chemical and Drug Induced Liver Injury; Halothane; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondria, Liver; Reverse Transcriptase Inhibitors; Risk Factors; Tacrine

Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

Topics: Adverse Drug Reaction Reporting Systems; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antitubercular Agents; Arylamine N-Acetyltransferase; Chemical and Drug Induced Liver Injury; Diclofenac; Floxacillin; Genetic Association Studies; Genetic Predisposition to Disease; HLA-B Antigens; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Phenotype; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors

The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. The natural history, characteristics and limitations of this exclusion process are revised. Also, the numerous published attribution algorithms for evaluation of drug-related liver abnormalities are described and their characteristics and differences are illustrated with true patients from our clinical experience. Situations that complicate the diagnosis such as age, sex, concomitant use of other drugs, genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs and drug-drug interactions are described. Finally, developing approach to diagnosis of drug-induced liver injury, different of attribution algorithms, are evaluated and explained using a new method based in a Bayesian approach developed and published by the authors. The authors' vision of all these potential advances and their clinical utility is provided.

Topics: Amoxicillin-Potassium Clavulanate Combination; Bayes Theorem; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Diseases; Male; Polymorphism, Genetic

There is a growing body of evidence that amoxicillin-clavulanic acid may induce severe adverse effects in patients.. A medline search of case reports and reviews on amoxicillin-clavulanic acid induced adverse effects was performed. The criteria of a consensus conference on the reporting of drug-induced liver disease were applied.. Amoxicillin-clavulanic acid has been associated with drug-induced cholestatic hepatitis in 208 reported patients. In 153 evaluable patients there were 106 males and 47 females with a mean age of 60 years (1-90). Liver associated co-morbidity and co-medication does not play a major part in the development of disease. In most instances respiratory tract infection and sinusitis were treated by amoxicillin-clavulanic acid with a mean treatment duration of 13.9 days and a reaction time until first onset of jaundice of 25.2 days average. Infection and cholestasis from other reason were ruled out in most patients. Liver injury was classified according to laboratory parameters to be hepatocellular in 35 patients, cholestatic in 24 patients and mixed in 83 patients. Normalization of liver enzymes was observed 11.5 weeks after onset of drug administration (average); three of 153 patients did not survive the adverse event.. Amoxicillin-clavulanic acid which is marketed for treatment of respiratory infections and sinusitis/otitis may in some cases induce severe adverse effects and death in patients of different age, especially if they are on multidrug regimens. In consideration of this fact many authors recommend to reflect carefully, whether amoxicillin-clavulanic acid is necessary in treatment of patients with localized or uncomplicated infections. If amoxicillin-clavulanic acid is prescribed, transaminase, alkaline phosphatase and bilirubin tests should be obtained within the first two weeks and after four to five weeks after beginning of treatment to recognize early enough undesired hepatic side effects.

Topics: Adolescent; Adult; Age Distribution; Americas; Amoxicillin-Potassium Clavulanate Combination; Asia; Australia; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cholestasis; Comorbidity; Europe; Female; Humans; Infant; Liver Diseases; Liver Failure; Male; Middle Aged; Respiratory Tract Infections; Retrospective Studies; Sex Distribution

Amoxicillin/clavulanic acid is a widely used antibiotic. Hepatic dysfunction is a rare adverse reaction associated with this combination antibiotic. We report the case of a 40-yr-old woman with a somewhat unusual presentation of amoxicillin/clavulanate-related cholestatic hepatotoxicity and multiple duodenal erosions whose diagnosis was delayed until inadvertent rechallenge with the antibiotic combination. The relevant literature is also reviewed and discussed. The diagnosis may be missed because the onset of signs/symptoms may occur several weeks after the cessation of therapy. The hepatic dysfunction, which may be severe and is more prevalent in elderly patients, is usually reversible, although chronic liver disease and deaths have been reported. Immunological hypersensitivity is considered to be the most likely mechanism resulting in liver injury. Amoxicillin/clavulanate should be used with caution in patients with underlying liver disease and in the elderly.

Topics: Acute Disease; Adult; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Therapy, Combination; Female; Humans; Recurrence; Sinusitis

Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS).. Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases.. Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10. We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

Topics: Alleles; Aminopeptidases; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Genetic Predisposition to Disease; Genome-Wide Association Study; HLA-A Antigens; HLA-DRB1 Chains; Humans; Liver; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22; Risk Factors

Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized.. We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system.. Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis.. Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury.. This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Diseases; Male; Phenotype; Veterans Health

Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin-clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)-linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de-identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory-based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)-9 and ICD 10th revision (ICD)-10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin-clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR-linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Azithromycin; Cephalexin; Chemical and Drug Induced Liver Injury; Ciprofloxacin; Humans; Population Health; Retrospective Studies; United States

We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug.. Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets.. The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated.. DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

Topics: Amoxicillin-Potassium Clavulanate Combination; Causality; Cefazolin; Chemical and Drug Induced Liver Injury; Computers; Cyproterone; Humans

A 68-year-old patient presented with symptoms of a urinary tract infection. A deterioration in the patient's liver function tests (LFTs) was noted 1 week following completion of a course of amoxicillin-clavunalate. This progressively worsened, reaching its peak by day 30. Our investigations excluded other possible causes for deranged LFTs and there was no improvement of same despite reduced dosing of potentially hepatotoxic medications.A trial of 30 mg/day prednisolone was commenced, resulting in an immediate and progressive improvement in LFTs to baseline over a period of 22 days and an improvement in constitutional symptoms such as tiredness and poor appetite. Drug-induced liver injury (DILI) is one of the common causes of acute hepatitis and a leading cause of acute liver failure in the US and Europe. Patterns of DILI can be generally divided into: (1) hepatocellular injury, (2) cholestatic injury and (3) mixed injury.

Topics: Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Europe; Humans; Liver; Prednisolone

The liver is susceptible to drug toxicity due to its vital role in xenobiotic metabolism and elimination. In addition to human leukocyte antigen (HLA) variants, which were previously determined as risk factors for drug-induced liver injury (DILI) due to co-amoxiclav, other non-HLA genes may contribute to hepatotoxicity risk. In this study, the association between DILI due to co-amoxiclav and several non-HLA genes was investigated. Association of variants in candidate genes (

Topics: Aged; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Glutathione Transferase; Humans; Loss of Function Mutation; Male; Middle Aged; Oxidative Stress; Polymorphism, Single Nucleotide; Superoxide Dismutase

Drug-induced liver injury (DILI) is a frequent cause of liver injury and acute liver failure. We aimed to review all hospitalized DILI cases in a tertiary Egyptian center from January 2015 through January 2016. Cases with elevated alanine aminotransferase more than 3-fold and/or alkaline phosphatase more than 2-fold the upper limit of normal value were prospectively recruited and followed for one year. Drug history, liver biopsy whenever feasible and application of Roussel Uclaf Causality Assessment Method (RUCAM) were the diagnostic prerequisites after exclusion of other etiologies of acute liver injury. In order of frequency, the incriminated drugs were: Diclofenac (31 cases, 41.3%), amoxicillin-clavulanate (14 cases, 18.7%), halothane toxicity (8 cases, 10.7%), ibuprofen (4 cases, 5.3%), Khat (3 cases, 4%), tramadol (3 cases, 4%), Sofosbuvir with ribavirin (2 cases, 2.7%), and acetylsalicylic acid (2 cases, 2.7%) with one offending drug in 93.3% of cases. Forty-four cases (58.7%) were males; while 56 cases (74.7%) had HCV related chronic liver disease. Thirty-two cases (42.7%) presented with pattern of hepatocellular injury, while 23 cases (30.7%) were with cholestasis, and 20 cases (20.7%) with a mixed hepatocellular/cholestatic injury. One case received a transplant (0.75%), 7 cases died (9.3%), 23 cases (30.6%) developed liver decompensation (hepatic encephalopathy and ascites), and 44 cases completely resolved (58.7%). In conclusion, Diclofenac is the commonest offender in DILI occurrence in an Egyptian cohort. Age and prothrombin concentration were the only predictors of unfavorable outcomes of DILI.

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Cyclooxygenase Inhibitors; Diclofenac; Egypt; Female; Hepatic Encephalopathy; Humans; Liver; Liver Failure, Acute; Male; Middle Aged; Prognosis; Prospective Studies; Tertiary Care Centers

A 41 years old woman with diagnosis of ADPKD had been in treatment with tolvaptan for 16 weeks when an elevation of liver enzyme levels was detected. She had taken autonomously amoxicillin/clavulanic acid (in doses of 825/175 mg twice a day for 7 days) about 5 weeks before. The timing of the event and the kind of hepatocellular injury could be attributed to the concomitance of medication of tolvaptan and amoxicillin/clavulanic acid.. We highlight the need to careful monitor hepatic enzyme levels in order to recognize early hepatic side effects in ADPKD patients in treatment with tolvaptan and amoxicillin/clavulanic acid.

Topics: Adult; Alanine Transaminase; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Antidiuretic Hormone Receptor Antagonists; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Liver; Polycystic Kidney, Autosomal Dominant; Tolvaptan

Acute kidney injury (AKI) often manifests in patients with liver disease because of a prerenal cause and presents as acute tubular necrosis or hepatorenal syndrome. Distinguishing between these entities is important for prognosis and treatment. Some patients may develop AKI related to their underlying liver disease: for example, membranoproliferative glomerulonephritis or IgA nephropathy. Bile cast nephropathy is an often ignored differential diagnosis of AKI in the setting of obstructive jaundice. It is characterized by the presence of bile casts in renal tubules, which can possibly cause tubular injury through obstructive and direct toxic effects. Thus, AKI in patients with liver disease may have a structural component in addition to a functional one.. In this study, we describe 2 patients with severe hyperbilirubinemia who developed AKI and underwent a kidney biopsy that revealed bile casts in tubular lumens, consistent with bile cast nephropathy.. One patient was treated aggressively for alcoholic hepatitis and required hemodialysis for AKI. The second patient was treated conservatively for drug-induced liver injury and did not require dialysis. Both patients saw a reduction in their bilirubin and creatinine toward baseline.. Bile cast nephropathy is an important pathological entity that may account for the renal dysfunction in some patients with liver disease. It requires kidney biopsy for diagnosis and may often be overlooked given the scarcity of kidney biopsy in this particular clinical setting. The etiology is multifactorial, and it is often difficult to predict without the aid of a renal biopsy.

Topics: Acute Kidney Injury; Adult; Aged, 80 and over; Amoxicillin-Potassium Clavulanate Combination; beta-Lactamase Inhibitors; Bile; Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Creatinine; Drug Therapy, Combination; Hepatitis, Alcoholic; Humans; Hyperbilirubinemia; Jaundice, Obstructive; Kidney Tubules; Liver; Male; Microscopy, Electron; Renal Dialysis; Ultrasonography

Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 β-galactosamide α-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

Topics: Amoxicillin-Potassium Clavulanate Combination; Cell Adhesion Molecules; Chemical and Drug Induced Liver Injury; Diclofenac; Floxacillin; Genome-Wide Association Study; Genotype; HLA-B Antigens; HLA-DQ beta-Chains; HLA-DRB1 Chains; Humans; Lapatinib; Liver; Proteins; Quinazolines

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Hepatitis; Humans; Male; Middle Aged

Amoxicillin-clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs.. Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials.. One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI.. AC-DILI causes a moderately severe, mixed hepatocellular-cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.

Topics: Age Factors; Alanine Transaminase; Alkaline Phosphatase; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Bilirubin; Black or African American; Chemical and Drug Induced Liver Injury; Cholestasis; Cohort Studies; Ethnicity; Female; Hispanic or Latino; Humans; Jaundice; Jaundice, Obstructive; Liver; Male; Middle Aged; Prospective Studies; Registries; Sex Distribution; Time Factors; United States; White People

Polypharmacy is common, and may modify mechanisms of drug-induced liver injury. We examined the effect of these drug-drug interactions on liver safety reports of four drugs highly associated with hepatotoxicity. In the WHO VigiBase™, liver event reports were examined for acetaminophen, isoniazid, valproic acid, and amoxicillin/clavulanic acid. Then, we evaluated the liver event reporting frequency of these 4 drugs in the presence of co-reported medications. Each of the 4 primary drugs was reported as having more than 2000 liver events, and co-reported with more than 600 different medications. Overall, the effect of 2275 co-reported drugs (316 drug classes) on the reporting frequency was analyzed. Decreased liver event reporting frequency was associated with 245 drugs/122 drug classes, including anti-TNFα, opioids, and folic acid. Increased liver event reporting frequency was associated with 170 drugs/82 drug classes; in particular, halogenated hydrocarbons, carboxamides, and bile acid sequestrants. After adjusting for age, gender, and other co-reported drug classes, multiple co-reported drug classes were significantly associated with decreased/increased liver event reporting frequency in a drug-specific/unspecific manner. In conclusion, co-reported medications were associated with changes in the liver event reporting frequency of drugs commonly associated with hepatotoxicity, suggesting that comedications may modify drug hepatic safety.

Topics: Acetaminophen; Adverse Drug Reaction Reporting Systems; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Data Mining; Databases, Factual; Drug Interactions; Isoniazid; Valproic Acid; World Health Organization

Drug-induced liver injury (DILI) frequently has a delayed onset with several human leukocyte antigen (HLA) genotypes affecting susceptibility, indicating a potential role for the adaptive immune system in the disease. The aim of this study was to investigate whether drug-responsive T lymphocytes are detectable in patients who developed DILI with the combination, antimicrobial amoxicillin-clavulanate. Lymphocytes from 6 of 7 patients were found to proliferate and/or secrete interferon-gamma (IFN-γ) when cultured with amoxicillin and/or clavulanic acid. Amoxicillin (n = 105) and clavulanic acid (n = 16) responsive CD4(+) and CD8(+) T-cell clones expressing CCR, chemokine (C-C motif) receptor 4, CCR9, and chemokine (C-X-C motif) receptor 3 were generated from patients with and without HLA risk alleles; no cross-reactivity was observed between the two drug antigens. Amoxicillin clones were found to secrete a heterogeneous panel of mediators, including IFN-γ, interleukin-22 and cytolytic molecules. In contrast, cytokine secretion by the clavulanic acid clones was more restricted. CD4(+) and CD8(+) clones were major histocompatability complex class II and I restricted, respectively, with the drug antigen being presented to CD4(+) clones in the context of HLA-DR molecules. Several pieces of evidence indicate that the clones were activated by a hapten mechanism: First, professional antigen-presenting cells (APCs) were required for optimal activation; second, pulsing APCs for 4-16 hours activated the clones; and third, inhibition of processing abrogated the proliferative response and cytokine release.. Both amoxicillin- and clavulanic acid-specific T cells participate in the liver injury that develops in certain patients exposed to amoxicillin-clavulanate.

Topics: Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Case-Control Studies; Cell Proliferation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Clavulanic Acid; Clone Cells; Female; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Reference Values; Sampling Studies

Ciprofloxacin and amoxicillin/clavulanic are two widely used antibiotics due to their high efficacy and few side effects. While the percentage of hepatotoxicity of these antibiotics is low, their frequent use has led to a progressive increase in the number of cases. Both antibiotics have been associated with a wide variety of hepatotoxic reactions, from a slight rise of transaminases to fulminant hepatitis. Once hepatotoxicity secondary to a drug appears, the first step is to discontinue the drug. Physicians may opt to administer an alternative treatment with a different chemical structure. It should be borne in mind, however, that different chemical structures may also cause recurrent drug-induced liver injuries (DILI). We present the case of a patient who consecutively developed DILI due to ciprofloxacin and amoxicillin/clavulanic.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Ciprofloxacin; Female; Humans; Middle Aged; Recurrence

Recent genome-wide association studies identified certain human leukocyote antigen (HLA) alleles as the major risk factors of drug-induced liver injuries (DILI). While these alleles often cause large relative risk, their predictive values are quite low due to low prevalence of idiosyncratic DILI. Finding additional risk factors is important for precision medicine. However, optimal design of further genetic studies is hindered by uncertain overall heritability of DILI. This is a common problem for low-prevalence pharmacological traits, since it is difficult to obtain clinical outcome data in families. Here we estimated the heritability (h(2)) of DILI from case-control genome-wide single nucleotide polymorphism data using a method based on random effect models. We estimated the proportion of h(2) captured by common SNPs for DILI to be between 0.3 and 0.5. For co-amoxiclav induced DILI, chromosome 6 explained part of the heritability, indicating additional contributions from common variants yet to be found. We performed simulations to assess the robustness of the h(2) estimate with limited sample size under low prevelance, a condition typical to studies on idiosyncratic pharmacological traits. Our findings suggest that common variants outside of HLA contribute to DILI susceptability; therefore, it is valuable to conduct further GWAS with expanded case collection.

Topics: Amoxicillin-Potassium Clavulanate Combination; beta-Lactamase Inhibitors; Case-Control Studies; Chemical and Drug Induced Liver Injury; Chromosomes, Human, Pair 6; Floxacillin; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.. High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.. The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).. HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

Topics: Adult; Aged; Alleles; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Genetic Association Studies; Genotype; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; HLA Antigens; Humans; Male; Middle Aged; Phenotype

Amoxicillin/clavulanate is a synthetic penicillin that is currently commonly used, especially for the treatment of respiratory and cutaneous infections. In general, it is a well-tolerated oral antibiotic. However, amoxicillin/clavulanate can cause adverse effects, mainly cutaneous, gastrointestinal, hepatic and hematologic, in some cases. Presented here is a case report of a 63-year-old male patient who developed cholestatic hepatitis after recent use of amoxicillin/clavulanate. After 6 wk of prolonged use of the drug, he began to show signs of cholestatic icterus and developed severe hyperbilirubinemia (total bilirubin > 300 mg/L). Diagnostic investigation was conducted by ultrasonography of the upper abdomen, serum tests for infection history, laboratory screening of autoimmune diseases, nuclear magnetic resonance (NMR) of the abdomen with bile duct-NMR and transcutaneous liver biopsy guided by ultrasound. The duration of disease was approximately 4 mo, with complete resolution of symptoms and laboratory changes at the end of that time period. Specific treatment was not instituted, only a combination of anti-emetic (metoclopramide) and cholestyramine for pruritus.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Antiemetics; Antipruritics; Biopsy; Chemical and Drug Induced Liver Injury; Cholangiopancreatography, Magnetic Resonance; Cholestasis, Intrahepatic; Humans; Hyperbilirubinemia; Jaundice; Male; Middle Aged; Risk Factors; Time Factors; Treatment Outcome

Liver cancers in children are primitive (hepatoblastoma, fibrolamellar hepatocarcinoma, sarcomas), or arise on a genetic or viral disease. Their treatment is a combination of chemotherapy (hepatoblastoma) and surgery. Neonatal hemangioendotheliomas may induce heart failure. They are now successfully treated with propranolol. Focal nodular hyperplasia is the most frequent benign tumour in older children and adolescents. Drug hepatotoxicity is not very frequent. Antipyretic drugs may induce severe side effects. Liver failure due to valproic acid is diagnostic of a respiratory chain disorder. The liver side effects of antituberculous and antiretroviral drugs should be monitored. Intestinal failure-associated liver disease is common and can be prevented or treated. Early referral to a specialized centre is important for the prognosis.

Topics: Acetaminophen; Amoxicillin-Potassium Clavulanate Combination; Analgesics, Non-Narcotic; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anti-Retroviral Agents; Anticonvulsants; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Humans; Intestinal Diseases; Liver Diseases; Liver Neoplasms; Mushroom Poisoning

The objectives of the present study were to determine the importance of amoxicillin-clavulanic acid (AC) hepatotoxicity in the paediatric population and to characterise the episodes identified and potential host-specific factors. This was addressed via a prospective observational study in which 8 Spanish hospitals participated.. A total of 11 cases were examined. For each patient included in the study, a structured and codified data-collection protocol was complied with, taking note of patient demographics, characteristics of the treatment assumed to provoke the reaction, concomitant medication, course and outcome of the episode, and laboratory variables during the reaction. The latter were determined every 6 months from the outset to the eventual resolution of the case.. A total of 11 cases of AC hepatotoxicity were detected, affecting 9 boys and 2 girls, ages 1 to 11 years. Causality criteria were assessed using the Council for International Organizations of Medical Sciences scale.. We conclude that the introduction of hepatotoxicity record systems in paediatric care, together with the continuing study and development of existing systems, would contribute to improving our epidemiological knowledge about the harmful effects of drugs on the liver.

Topics: Adverse Drug Reaction Reporting Systems; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Incidence; Infant; Male; Prospective Studies; Qualitative Research; Spain

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Liver Function Tests; Male; Middle Aged; Recurrence

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Anti-Infective Agents; Anticholesteremic Agents; Autoantibodies; Chemical and Drug Induced Liver Injury; Diagnostic Techniques, Digestive System; Female; Genes, MHC Class II; Hepatitis, Autoimmune; Humans; Immunoglobulins; Jaundice; Liver; Liver Failure, Acute; Male; Registries

Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction.. We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background.. AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)).. Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

Topics: Adaptive Immunity; Aged; Aged, 80 and over; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Chi-Square Distribution; Europe; Female; Gene Frequency; Genes, MHC Class I; Genes, MHC Class II; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; HLA-A Antigens; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Registries; Risk Assessment; Risk Factors; United States; White People

Amoxicillin-clavulanate is the most common drug involved in drug-induced liver injury and the single most frequently prescribed product leading to hospitalization for drug-induced liver disease in Spain. The liver damage most frequently associated with amoxicillin-clavulanate is cholestasic type. The latency period between first intake and onset of symptoms is 3-4 weeks on average. A 76-year-old man developed fever, pruritus, and jaundice 3 weeks after having completed treatment with amoxicillin-clavulanate. Liver function tests showed cholestasic hepatitis (up to 50.75 mg/dL of total serum bilirubin level). The ultrasound-guided liver biopsy revealed severe canalicular cholestasis and portal and lobular eosinophilic infiltrates. Prednisone and ursodeoxycholic acid therapy were then prescribed. The patient became symptom-free with normal liver function tests. Amoxicillin-clavulanate can cause hepatocellular, cholestasic, or mixed liver injury. The presence of eosinophilic infiltrates in the liver biopsy and the clinical signs of hypersensitivity in some of the cholestasic cases suggest a pathophysiological immunoallergic mechanism. For this reason, corticosteroid treatment should be considered for patients with severe cholestasic liver injury.

Topics: Aged; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Drug Therapy, Combination; Glucocorticoids; Humans; Liver Function Tests; Male; Prednisone; Treatment Outcome; Ursodeoxycholic Acid

Co-amoxiclav is one of the most common causes of drug-induced liver injury (DILI). Although there are previous reports of genetic associations between HLA class II and co-amoxiclav-related DILI, studies to date have been based on very small numbers from single centres only. In order to address this problem we have investigated the role of HLA class II DRB1 and DQB1 in 61 cases of co-amoxiclav DILI as part of a UK-wide multicentre study.. HLA alleles and genotypes were compared with those of 40 individuals exposed to co-amoxiclav without toxicity (treated controls) and 191 population controls.. There were two significant findings from the study. First, HLA-DRB1*15 was increased in patients (53%) versus both treated (33%: OR=2.29: 95% CI: 1.00-5.26) and population controls (30%: OR=2.59:95% CI: 1.44-4.68: p=0.002). Second, DRB1*07 was found to be reduced in patients (9.8%) compared to both treated (35%: OR=0.18: 95% CI: 0.06-0.52: p=0.0011, pc=0.0154) and population controls (29%: OR=0.266: 95% CI: 0.11-0.65: p=0.0019, pc=0.0266).. These results confirm the previously reported significant genetic risk for HLA-DRB1*15 and also provide evidence of a protective effect of the HLA-DRB1*07 family of alleles. HLA alleles and haplotypes may be particularly important in susceptibility and resistance to co-amoxiclav-DILI, but it remains to be seen whether this effect is due to the identified alleles or others in close linkage disequilibrium elsewhere on the MHC.

Topics: Aged; Alleles; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Genes, MHC Class II; Genetic Predisposition to Disease; Genotype; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Male; Middle Aged; Risk Factors

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Genetic Predisposition to Disease; HLA Antigens; Humans

Topics: Amoxicillin-Potassium Clavulanate Combination; Anesthetics, Inhalation; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Halothane; Humans; Jaundice, Obstructive; Liver Failure, Acute; Liver Transplantation; Postoperative Complications; Sulfonamides; Time Factors

Topics: Acute Disease; Adult; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Male

Liver damage associated with the amoxicillin-clavulanate combination is more frequent in patients over the age of 50 and during long-term treatment. It is mainly due to the clavulanic acid component of the drug. It is better to reserve this combination for infections due to bacteria that are resistant to amoxicillin.

Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Child; Drug Combinations; France; Humans; Middle Aged

The aim of our study was to compare three search strategies using a computerized administrative database to identify cases of idiosyncratic drug-induced liver injury (DILI) due to amoxicillin/clavulanic acid, phenytoin, valproic acid, and isoniazid.. In search 1, electronic medical records from patients seen between 1994 and 2004 with an ICD-9-CM code of acute liver injury were identified and cross-searched for the specific drug names in the dictation text. In search 2, all patients with an ICD-9-CM code of drug poisoning/overdose due to one of the four study drugs were identified. In search 3, patients with a poisoning code as well as an acute liver injury code were identified.. Review of the records from the 7,395 search 1 patients yielded 51 DILI cases (0.7%). In contrast, the 566 search 2 patients yielded only three DILI cases (0.5%). Finally, search 3 provided the greatest specificity but a low rate of detection with only two patients (3.9%) having DILI due to one of the four drugs.. Acute liver injury ICD-9-CM codes combined with a text search of the dictated medical record yielded the greatest number of DILI cases but was less specific than crossing acute liver injury and poisoning codes. Use of ICD-9-CM codes to identify rare adverse events like DILI remains problematic and highlights the need for prospective surveillance networks.

Topics: Adolescent; Adult; Aged; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant; International Classification of Diseases; Isoniazid; Liver Diseases; Male; Medical Records Systems, Computerized; Michigan; Middle Aged; Phenytoin; Population Surveillance; Sensitivity and Specificity; United States; Valproic Acid

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholelithiasis; Cholestasis, Extrahepatic; Clozapine; Diagnosis, Differential; Gallstones; Humans; Lithium Compounds; Liver Function Tests; Male; Middle Aged; Periapical Abscess; Schizophrenia, Paranoid; Suicide, Attempted; Transaminases; Trichloroethylene

Amoxicillin-clavulanate (AC) hepatotoxicity has been reported to exhibit a higher predominance of cholestatic types of damage, especially in males. However, the determinants of its clinical expression are unknown. This study prospectively evaluated the profile of AC hepatotoxicity. Data on all cases of hepatotoxicity reported to the Spanish Registry attributed to AC and assessed as definite or probable on the Council for International Organizations of Medical Sciences (CIOMS) scale were collated and compared to published case series. Hepatotoxicity related to amoxicillin-clavulanate was identified in 69 patients (36 males; mean age 56 years) representing 14% of all cases of hepatotoxicity submitted to the Registry. There was an overall sex distribution and the predominant pattern of lesion was hepatocellular (36%) which occurred at a shorter duration of treatment (P < .03). Mean time lapse between therapy initiation and jaundice onset was 16 days. Late onset of symptoms following end of treatment occurred in half the cases. Multiple logistic regression analysis identified advancing age as the factor associated with the development of cholestatic/mixed type of injury (odds ratio for an age interval for 1 year: 1.045 [95% CI = 1.013-1.078; P = .005). An unfavorable outcome was seen in 7% of patients. In conclusion, age is the most important determinant in the biochemical expression of AC hepatotoxicity; younger age is associated with cytolytic damage and shorter treatment duration, whereas cholestatic/mixed type of damage is related to older age and prolonged AC therapy.

Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Liver; Liver Diseases; Logistic Models; Male; Middle Aged; Prospective Studies; Spain

A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin-clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage.

Topics: Adult; Aged; Aged, 80 and over; Amoxicillin-Potassium Clavulanate Combination; Atorvastatin; Azepines; Captopril; Cardiovascular Agents; Central Nervous System Agents; Chemical and Drug Induced Liver Injury; Chronic Disease; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Heptanoic Acids; Humans; Liver; Liver Diseases; Male; Middle Aged; Pyrroles; Registries; Spain

Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases.. A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed.. Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001).. Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.

Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Amoxicillin-Potassium Clavulanate Combination; Analysis of Variance; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Liver; Liver Diseases; Liver Failure; Male; Middle Aged; Odds Ratio; Probability; Proportional Hazards Models; Registries; Retrospective Studies; Risk Assessment; Sex Distribution; Spain; Survival Analysis

Topics: Aged; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Male

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Therapy, Combination; Humans; Terminology as Topic

We describe an elderly patient with normal pre-existing liver functions who was treated with amoxicillin/clavulanic acid and later ciprofloxacin for acute bronchitis. He developed a pattern of liver dysfunction consistent with hepatocellular injury, with clinical features of a hypersensitivity reaction, which may be attributable to either or both of the antimicrobial agents used. This gradually resolved over a 4-week time period, with conservative management. A review of the relevant literature on drug-induced hepatotoxicity is also presented.

Topics: Aged; Aged, 80 and over; Alanine Transaminase; Alkaline Phosphatase; Amoxicillin-Potassium Clavulanate Combination; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ciprofloxacin; Humans; Male

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Therapy, Combination; Humans; Male; Middle Aged

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Diagnosis, Differential; Humans; Jaundice; Male; Middle Aged

Amoxicillin-clavulanic acid is a commonly used antibiotic in clinical practice. It is usually prescribed on an empirical basis and several cases of hepatotoxicity with cholestasis have been described. We report the case of a 42-year-old man who developed an acute hepatocellular lesion with progression to cirrhosis. The patient received amoxicillin-clavulanic acid twice with an interval of four months. Other causes of hepatic failure were excluded. Although amoxicillin-clavulanic acid-induced hepatotoxicity has been widely documented, there are no other reports describing its progression to cirrhosis in an adult.

Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Humans; Liver Cirrhosis; Male

Toxic hepatitis secondary to amoxycillin-clavulanic acid is an infrequent clinical picture. Most of the cases are reported to have a benign course. We report two cases of severe hepatic failure following amoxycillin-clavulanic acid use. One of the cases had cholestatic features primarily, and the other had hepatocellular injury prominently. The first case had also findings of trombotic trombositic purpura and had a fatal course.

Topics: Adult; Aged; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Jaundice; Male

We are describing a case of undesired side effect of the cure (toxic hepatocellular damage) by Augmentin. The main symptoms were jaundice and pruritus. This is the next documented case of the hepatocellular damage by Augmentin in Poland. In the conclusion, we draw the attention to the role of interview in the diagnosis of the illness described and therapeutic management.

Topics: Aged; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Jaundice; Liver Diseases; Male; Pruritus

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Liver; Middle Aged

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Erysipelas; Fatal Outcome; Female; Humans; Liver Cirrhosis; Middle Aged

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Male; Middle Aged; Pruritus

Topics: Adverse Drug Reaction Reporting Systems; Amoxicillin-Potassium Clavulanate Combination; Australia; Chemical and Drug Induced Liver Injury; Humans; Prevalence

Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Severity of Illness Index

Topics: Adult; Adverse Drug Reaction Reporting Systems; Amoxicillin-Potassium Clavulanate Combination; Anesthetics, Inhalation; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antifungal Agents; Appetite Depressants; Arrhythmias, Cardiac; Biliary Tract Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; General Practice, Dental; Heart Valve Diseases; Humans; Macrolides; Sulfonamides

Topics: Aged; Amoxicillin-Potassium Clavulanate Combination; Bile Ducts, Intrahepatic; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Drug Therapy, Combination; Female; Humans; Time Factors

Topics: Acute Disease; Aged; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Biopsy; Chemical and Drug Induced Liver Injury; Cholangitis; Drug Therapy, Combination; Humans; Liver; Male

Increase of acute liver injury in patients taking amoxicillin-clavulanic acid (co-amoxiclav) as compared to those taking amoxicillin has been suggested. To further investigate the potential hepatotoxicity of the two drugs a historical cohort study was conducted in the Italian region of Friuli-Venezia Giulia. One hundred and eighteen potential cases of acute liver injury were identified through the regional hospital information system and medical records were reviewed for all of them. Overall, 12 cases of acute liver injury were identified: 3 cases occurred in the amoxicillin exposure category, 2 among co-amoxiclav group, and 7 in the non-use category. The adjusted estimate of the rate ratio was 5.7 (CI 95% 1.5-22.1) among users of amoxicillin alone and 6.2 (CI 95% 1.3-29.7) among users of co-amoxiclav.

Topics: Acute Disease; Adolescent; Adult; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Cohort Studies; Drug Therapy, Combination; Female; Hospitalization; Humans; Incidence; Italy; Male; Middle Aged; Penicillins; Risk

We report a 72 years old diabetic male that, after the use of combined amoxicillin-clavulanic acid, developed pruritus and jaundice. Liver function tests showed serum total bilirubin of 4.3 mg/dL aspartate aminotransferase 140 U/l (normal < 35 U/L), alanine aminotransferase 470 U/L (normal < 40) and alkaline phosphatases of 400 U/L (normal < 100). Serology for hepatitis A, B and C viruses was negative, ERCP showed a normal biliary tree and liver biopsy disclosed a cholestatic hepatitis. Ursodeoxycholic was started to relieve pruritus. Liver function tests improved shortly thereafter, suggesting that this drug may be useful in the treatment of drug induced cholestasis.

Topics: Aged; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Drug Therapy, Combination; Follow-Up Studies; Humans; Liver; Male; Ursodeoxycholic Acid

Since first description in 1988, numerous cases of amoxycillin-clavulanic acid hepatotoxicity have been reported. Most of them are cholestatic hepatitis. A case of acute hepatocellular injury by amoxycillin-clavulanic acid is reported in a 23-years-old male, with a favourable outcome after 18 weeks.

Topics: Acute Disease; Adult; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Male

Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Clavulanic Acids; Drug Therapy, Combination; Humans; Penicillins

We report eight cases of liver injury related to amoxycillin-clavulanate. Liver biopsy performed in seven patients revealed varying degrees of injury to interlobular bile ducts in all cases. Lesions included irregularity of the nuclei, vacuolization of the cytoplasm, lymphocytic infiltration, destruction and endothelialization of the bile duct epithelium. Ductopenia was not observed. In two patients liver injury was accompanied by prominent extrahepatic manifestations (acute interstitial nephritis in one and acute lacrimal gland inflammation and sialadenitis with prolonged xerostomia in the other). We conclude that interlobular bile-duct lesions of varying severity are a common feature in liver injury related to amoxycillin-clavulanate. Side effects of the drug include acute interstitial nephritis and sialadenitis.

Topics: Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Bile Ducts, Intrahepatic; Chemical and Drug Induced Liver Injury; Clavulanic Acids; Drug Therapy, Combination; Female; Humans; Inflammation; Lacrimal Apparatus Diseases; Male; Middle Aged; Nephritis, Interstitial; Sialadenitis; Xerostomia

Two cases (first cases from Poland and Eastern Europe) with liver injury due to amoxycillin-clavulanic acid (augmentin) are reported. Pruritus and jaundice were the main symptoms. Liver biopsy revealed mixed hepatocellular-cholestatic liver injury in both cases. In addition, in one case the microgranulomalike aggregate of inflammatory cells was found. Clinical and laboratory abnormalities returned to normal within 13 weeks.

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Clavulanic Acid; Clavulanic Acids; Drug Combinations; Drug Therapy, Combination; Female; Granuloma; Humans; Male; Middle Aged; Respiratory Tract Infections; Tonsillitis

This 70-year-old man experienced an episode of cholestatic hepatitis most likely due to an immunologically mediated reaction to amoxicillin-clavulanate. The episode occurred after cessation of the drug combination. Duration of illness was 16 weeks, and the patient recovered completely.

Topics: Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Clavulanic Acids; Drug Therapy, Combination; Humans; Liver Function Tests; Male; Sinusitis

Topics: Adverse Drug Reaction Reporting Systems; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Clavulanic Acids; Drug Therapy, Combination; Female; Floxacillin; Humans; Middle Aged

Fifteen cases of hepatitis related to a combination of amoxycillin and clavulanic acid are reported. Most patients were aged 60 years or more and there were more men than women (sex ratio 4:1). The amoxycillin-clavulanic acid had been given at doses ranging from 0.5 to 6 g/day (mean 2 g/day) for seven to 60 days (mean 18 days). In 11 cases, the first symptoms appeared one to four weeks after stopping treatment. Jaundice was observed in all patients and was frequently associated with pruritus. Serum aminotransferase activities were increased in all patients and were generally two to 10 times the upper limit of normal. Serum alkaline phosphatase activity was considerably increased, from two to seven times the upper limit of normal. Histological examination of the liver, performed in seven patients, showed centri- or panlobular cholestasis in all cases, associated with granulomatous hepatitis in one. The prognosis of amoxycillin-clavulanic acid induced hepatitis seemed to be good. None of the patients exhibited biological or clinical features of hepatic failure and the course of the disease was characterised by the resolution of jaundice within one to eight weeks and a complete recovery within four to 16 weeks. Taking into account the number of treated subjects and reported cases, we estimated the risk of developing hepatitis with this drug combination to be very low, probably below 1/100,000. Our data suggest that the risk of hepatotoxicity may be increased in elderly men given lengthy treatment. The association of hepatitis and signs of hypersensitivity may suggest an immunoallergic mechanism of hepatotoxicity in some patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Clavulanic Acids; Drug Therapy, Combination; Female; Humans; Jaundice; Male; Middle Aged; Pruritus; Sex Factors; Time Factors

Topics: Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Clavulanic Acids; Drug Therapy, Combination; Humans; Male

To report a case of death due to Augmentin-induced cholestatic hepatitis and discuss a possible drug interaction between Augmentin and oestrogenic steroids.. An 81-year-old man, on oestrogen therapy for prostatic malignancy, presented with obstructive jaundice one week after completing a four-week course of Augmentin for recurrent urinary tract infection. Liver biopsy showed features of a drug-induced cholestatic hepatitis with bile duct injury. His clinical course was marked by progressive deterioration with increasing jaundice and the development of hepatic encephalopathy. A course of prednisolone did not result in any improvement and he died nine weeks after the onset of jaundice.. The cholestatic hepatitis induced by Augmentin is usually reversible but may be progressive, leading to death. The concurrent administration of ethinyloestradiol, a potentially cholestatic agent, may have altered the susceptibility and/or course of the reaction in this patient.

Topics: Aged; Aged, 80 and over; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Clavulanic Acids; Drug Interactions; Estradiol Congeners; Humans; Male; Prostatic Neoplasms; Urinary Tract Infections

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis; Clavulanic Acids; Drug Therapy, Combination; Humans

Topics: Adult; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis, Extrahepatic; Clavulanic Acids; Drug Therapy, Combination; Female; Humans

Five case histories are presented of patients developing cholestatic hepatitis associated with the intake of the antibiotic combination agent amoxicillin and clavulanic acid (Augmentin). In two of these cases, signs of hepatic injury recurred after readministration of this combination but not after the intake of amoxicillin alone. In none of the patients was another cause for cholestatic hepatitis found and extrahepatic causes were excluded by ultrasonography, CT scanning, or ERCP. Most viral causes of hepatic injury were excluded in these patients. With the exception of one patient, who developed a transient rash, no immunoallergic signs were present. Biopsy in two patients showed extensive cholestasis without significant necrosis. Clavulanic acid seems to be responsible for this adverse effect.

Topics: Aged; Alanine Transaminase; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Child, Preschool; Cholestasis, Intrahepatic; Clavulanic Acids; Drug Therapy, Combination; Humans; Male; Middle Aged; Time Factors

Topics: Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Clavulanic Acids; Drug Therapy, Combination; Humans; Male