Hyperbilirubinemia During Quinupristin-Dalfopristin Therapy
Hyperbilirubinemia During Quinupristin-Dalfopristin Therapy
Study Objective. To review the liver histopathology in transplant recipients who developed hyperbilirubinemia during therapy with quinupristin-dalfopristin, a new streptogramin antibiotic, and to ascertain whether objective histologic evidence of adverse drug effect could be correlated to serum bilirubin levels.
Design. Retrospective analysis.
Setting. University of Pittsburgh Medical Center.
Patients. From a database of 34 liver recipients who received quinupristin-dalfopristin for vancomycin-resistant Enterococcus faecium infection who were prospectively enrolled in a multicenter, open-label, emergency-use protocol, the data for a subset of 25 patients who underwent one or more liver biopsies during therapy were reviewed for this study.
Interventions. Quinupristin-dalfopristin was administered intravenously at 7.5 mg/kg every 8 hours. Available serum bilirubin levels from before, during, and 1 week after therapy were tabulated. Liver biopsy results obtained within 1 week before and during therapy were retrospectively reviewed. Histopathologic results were characterized and correlated to bilirubin level.
Measurements and Main Results. Cholestatic changes were already present in 15 of 17 patients who underwent biopsy before therapy. During therapy, the most common findings from 40 biopsies (25 patients) were cholestasis (33 biopsies), acute rejection (10), and periportal inflammation (8). There was no evidence of drug-specific histopathologic injury.
Conclusion. Hyperbilirubinemia in these patients was likely multifactorial and most frequently due to sepsis and prior graft injury.
In recent years, the rate of antibiotic resistance for many clinically important gram-positive strains of bacteria has been rising, with vancomycin-resistant enterococci implicated in an increasing percentage of nosocomial infections since the late 1980s. A recent surveillance report of bloodstream infections in the United States from 1995-1998 ranked enterococci as the third most frequent pathogen, with 50% of Enterococcus faecium strains exhibiting high-level resistance to vancomycin. These infections are a particular problem in immunocompromised patients, including liver transplant recipients, for whom vancomycin-resistant enterococci are associated with very high morbidity and mortality.
The emergence of multidrug-resistant pathogens has given urgency to the development of new antimicrobials with the potential for activity against these organisms. One such agent is quinupristin-dalfopristin (Synercid; Aventis Pharmaceuticals, Bridgewater, NJ), a strep-togramin active against most gram-positive organisms. Quinupristin-dalfopristin is active against staphylococci, including methicillin-resistant strains; streptococci, including penicillin-resistant strains; and E. faecium, including those with high-level glycopeptide resistance.
Conjugated hyperbilirubinemia was reported in phase III clinical trials of quinupristin-dalfopristin, although this was in the absence of any prospective histopathologic (liver biopsy) investigation. Data from phase III comparative and noncomparative trials with quinupristin-dalfopristin did not demonstrate significant elevations of either hepatic transaminase (aspartate aminotransferase, alanine amino-transferase) levels or alterations in liver synthetic function tests (serum albumin level or prothrombin time).
Liver transplant recipients with serious or life-threatening infection due to vancomycin-resistant enterococci have received quinupristin-dalfopristin therapy on an emergency-use basis. The elevation of serum bilirubin level is a common laboratory finding in liver transplant recipients, particularly in the setting of concomitant critical illness. In this complex population, hyperbilirubinemia may be due to single or multiple factors.
Study Objective. To review the liver histopathology in transplant recipients who developed hyperbilirubinemia during therapy with quinupristin-dalfopristin, a new streptogramin antibiotic, and to ascertain whether objective histologic evidence of adverse drug effect could be correlated to serum bilirubin levels.
Design. Retrospective analysis.
Setting. University of Pittsburgh Medical Center.
Patients. From a database of 34 liver recipients who received quinupristin-dalfopristin for vancomycin-resistant Enterococcus faecium infection who were prospectively enrolled in a multicenter, open-label, emergency-use protocol, the data for a subset of 25 patients who underwent one or more liver biopsies during therapy were reviewed for this study.
Interventions. Quinupristin-dalfopristin was administered intravenously at 7.5 mg/kg every 8 hours. Available serum bilirubin levels from before, during, and 1 week after therapy were tabulated. Liver biopsy results obtained within 1 week before and during therapy were retrospectively reviewed. Histopathologic results were characterized and correlated to bilirubin level.
Measurements and Main Results. Cholestatic changes were already present in 15 of 17 patients who underwent biopsy before therapy. During therapy, the most common findings from 40 biopsies (25 patients) were cholestasis (33 biopsies), acute rejection (10), and periportal inflammation (8). There was no evidence of drug-specific histopathologic injury.
Conclusion. Hyperbilirubinemia in these patients was likely multifactorial and most frequently due to sepsis and prior graft injury.
In recent years, the rate of antibiotic resistance for many clinically important gram-positive strains of bacteria has been rising, with vancomycin-resistant enterococci implicated in an increasing percentage of nosocomial infections since the late 1980s. A recent surveillance report of bloodstream infections in the United States from 1995-1998 ranked enterococci as the third most frequent pathogen, with 50% of Enterococcus faecium strains exhibiting high-level resistance to vancomycin. These infections are a particular problem in immunocompromised patients, including liver transplant recipients, for whom vancomycin-resistant enterococci are associated with very high morbidity and mortality.
The emergence of multidrug-resistant pathogens has given urgency to the development of new antimicrobials with the potential for activity against these organisms. One such agent is quinupristin-dalfopristin (Synercid; Aventis Pharmaceuticals, Bridgewater, NJ), a strep-togramin active against most gram-positive organisms. Quinupristin-dalfopristin is active against staphylococci, including methicillin-resistant strains; streptococci, including penicillin-resistant strains; and E. faecium, including those with high-level glycopeptide resistance.
Conjugated hyperbilirubinemia was reported in phase III clinical trials of quinupristin-dalfopristin, although this was in the absence of any prospective histopathologic (liver biopsy) investigation. Data from phase III comparative and noncomparative trials with quinupristin-dalfopristin did not demonstrate significant elevations of either hepatic transaminase (aspartate aminotransferase, alanine amino-transferase) levels or alterations in liver synthetic function tests (serum albumin level or prothrombin time).
Liver transplant recipients with serious or life-threatening infection due to vancomycin-resistant enterococci have received quinupristin-dalfopristin therapy on an emergency-use basis. The elevation of serum bilirubin level is a common laboratory finding in liver transplant recipients, particularly in the setting of concomitant critical illness. In this complex population, hyperbilirubinemia may be due to single or multiple factors.
Source...