amoxicillin-potassium-clavulanate-combination and Drug-Related-Side-Effects-and-Adverse-Reactions

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

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

To evaluate the efficacy and safety of CLAVAMOX dry syrup (potassium clavulanate/amoxicillin) in children with otitis media, we conducted a postmarketing surveillance from February to September 2006. The analysis was made on the basis of 470 survey sheets collected from 127 medical institutions, of which we investigated 455 cases for safety, and 433 cases for efficacy. The efficacy was 95.2% in the 433 subjects eligible for the efficacy analysis. The clinical improvement rates for major symptoms (otalgia, otorrhea, flare reaction of drum membrane and fever) were 95% or more. The efficacies for the three major offending bacteria of otitis media (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were between 94.6% and 100%. The efficacies for penicillin-resistant Streptococcus pneumoniae (PRSP) and penicillin intermediate resistant Streptococcus pneumoniae (PISP) were 95% or more. Adverse drug reactions (ADRs) were reported in 106 (23.3%) of the 455 subjects eligible for safety analysis. The major ADRs were diarrhea, of which incident was 22.6% (103 of 455). These ADRs were observed at a higher rate in younger age patients. Most of the diarrhea cases were non-serious, reversible on discontinuation or continuation of the drug. No clinically important serious diarrhea cases such as pseudomembranous colitis or dehydration were observed. Our surveillance results demonstrated that CLAVAMOX dry syrup had excellent efficacy and clinically manageable safety in children with otitis media. These findings indicated that this medicine was clinically-useful in children with otitis media.

Topics: Amoxicillin-Potassium Clavulanate Combination; Child; Child, Preschool; Dosage Forms; Drug-Related Side Effects and Adverse Reactions; Female; Haemophilus influenzae; Humans; Infant; Male; Moraxella catarrhalis; Otitis Media; Product Surveillance, Postmarketing; Prospective Studies; Streptococcus pneumoniae

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: 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

To review spontaneous reports of drug-associated adverse hepatic reactions.. Reports of drug-associated adverse hepatic reactions received by the New Zealand Centre for Adverse Reactions Monitoring over the 21 year period January 1974 to December 1994 were reviewed. Subdivision into three 7 year periods was undertaken to compare patterns.. Of a total of 22,455 adverse medicine reaction (AMR) reports there were 943 reports of liver injury (4.2%). Two hundred and five drugs were associated with hepatic reactions. The top 20 drugs accounted for 57% of all liver reactions. Fifty-seven percent were reported in females. Hepatotoxicity was most commonly reported among patients 50-80 years old. Liver reactions were associated with a 3.3% mortality, but were responsible for 7.4% of all fatal occurrences. There was a steady increase in the number of reports over the 21 years. Although the largest number of reports of liver injury were received between 1988 and 1994, mortality was lowest during this period. There were substantial differences in the medicines associated with hepatic reactions during each of the three periods, although erythromycin was the commonest cause throughout. Erythromycin was associated with two deaths. Halothane and perhexilene were the most frequent cause of death and were two of the most important causes of liver injury during the first and second periods. Diclofenac, Augmentin and flucloxacillin were important causes of hepatotoxicity during period 3 but were not associated with a fatal outcome.. Hepatic reactions accounted for 4.2% of all adverse medicine reactions and 7.4% of all fatal occurrences. The top 20 drugs were responsible for 57% of all liver reactions. Despite a steady increase in the number of reports during the 21 years, mortality was lowest during the last 7 years. Differences in the medicines causing liver injury during the three periods influenced the number of fatalities. Erythromycin was the most commonly reported cause of hepatic reactions but was usually associated with a favourable outcome. There were no reported deaths with diclofenac, Augmentin or flucloxacillin.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Aged, 80 and over; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Anesthetics, Inhalation; Anti-Bacterial Agents; Anti-Inflammatory Agents; Calcium Channel Blockers; Cardiovascular Agents; Cause of Death; Clavulanic Acids; Diclofenac; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Female; Floxacillin; Halothane; Humans; Liver; Male; Middle Aged; New Zealand; Penicillins; Perhexiline; Steroids