Amy Schilling, PharmD

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

 

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

 

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

In the past half-century, vancomycin has gone from near-orphan status to being one of the most often used antibiotics in our formulary. The driving force for its use is clear: the evolution of Staphylococcus aureus. At first, vancomycin was used to treat infections caused by penicillin-resistant strains. However, the discovery of methicillin curbed its use for more than 2 decades.¹

Then, as methicillin-resistant S aureus (MRSA) began to spread in the 1980s, the use of vancomycin began to increase, and with the rise in community-associated MRSA infections in the 1990s, it became even more widely prescribed. The recent Infectious Diseases Society of America (IDSA) guidelines for treatment of infections due to MRSA are replete with references to the use of vancomycin.²

Another factor driving the use of vancomycin is the increased prevalence of device-associated infections, many of which are caused by coagulase-negative staphylococci and other organisms that colonize the skin.³ Many of these bacteria are susceptible only to vancomycin; they may be associated with infections of vascular catheters, cardiac valves, pacemakers, implantable cardioverter-defibrillators, orthopedic implants, neurosurgical devices, and other devices.

To use vancomycin appropriately, we need to recognize the changing minimum inhibitory concentrations (MICs), to select proper doses and dosing intervals, and to know how to monitor its use. Despite more than 50 years of experience with vancomycin, we sometimes find ourselves with more questions than answers about its optimal use.

WHAT IS VANCOMYCIN?

Vancomycin is a glycopeptide antibiotic isolated from a strain of Streptomyces orientalis discovered in a soil sample from Borneo in the mid-1950s.¹ It exerts its action by binding to a d-alanyl-d-alanine cell wall precursor necessary for peptidoglycan cross-linking and, therefore, for inhibiting bacterial cell wall synthesis.

Vancomycin is bactericidal against most gram-positive species, including streptococci and staphylococci, with the exception of Enterococcus species, for which it is bacteriostatic. Though it is bactericidal, it appears to kill bacteria more slowly than beta-lactam antibiotics, and therefore it may take longer to clear bacteremia.⁴

WHAT IS THE BEST WAY TO DOSE VANCOMYCIN?

Vancomycin is widely distributed to most tissues, with an approximate volume of distribution of 0.4 to 1 L/kg; 50% to 55% is protein-bound. Because of this large volume of distribution, vancomycin’s dosing is based on actual body weight.

Vancomycin is not metabolized and is primarily excreted unchanged in the urine via glomerular filtration. It therefore requires dosage adjustments for renal insufficiency.

Vancomycin’s molecular weight is 1,485.73 Da, making it less susceptible to removal by dialysis than smaller molecules. Dosing of vancomycin in patients on hemodialysis depends on many factors specific to the dialysis center, including but not limited to the type of filter used, the duration of filtration, and whether high-flux filtration is used.

Is continuous intravenous infusion better than standard dosing?

Giving vancomycin by continuous infusion has been suggested as a way to optimize its serum concentration and improve its clinical effectiveness.

Wysocki et al⁵ conducted a multicenter, prospective, randomized study comparing continuous and intermittent intravenous infusions of vancomycin (the latter every 12 hours) to treat severe hospital-acquired MRSA infections, including bloodstream infections and pneumonia. Although blood concentrations above 10 μg/mL were reached more than 30 hours faster with continuous infusions than with intermittent ones, the microbiologic and clinical outcomes were similar with either method.

James et al⁶ compared the pharmacodynamics of conventional dosing of vancomycin (ie, 1 g every 12 hours) and continuous infusion in 10 patients with suspected or documented gram-positive infections in a prospective, randomized, crossover study. While no adverse effects were observed, the authors also found no statistically significant difference between the treatment groups in the pharmacodynamic variables investigated, including the area under the curve (AUC) divided by the MIC (the AUC-MIC ratio).

In view of the currently available data, the guidelines for monitoring vancomycin therapy note that there does not appear to be any difference in patient outcomes with continuous infusion vs intermittent dosing.⁷

Should a loading dose be given?

Another proposed strategy for optimizing vancomycin’s effectiveness is to give a higher initial dose, ie, a loading dose.

Wang et al⁸ performed a single-center study in 28 patients who received a 25 mg/kg loading dose at a rate of 500 mg/hour. This loading dose was safe, but the authors did not evaluate its efficacy.

Mohammedi et al⁹ compared loading doses of 500 mg and 15 mg/kg in critically ill patients receiving vancomycin by continuous infusion. The weight-based loading dose produced higher post-dose levels and a significantly higher rate of clinical cure, but there was no significant difference in the rate of survival to discharge from the intensive care unit.

While the use of a loading dose appears to be safe and likely leads to more rapid attainment of therapeutic blood levels, we lack data on whether it improves clinical outcomes, and further study is needed to determine its role.

 

WHAT IS THE BEST WAY TO MONITOR VANCOMYCIN THERAPY?

Whether and how to use the serum vancomycin concentration to adjust the dosing has been a matter of debate for many years. Convincing evidence that vancomycin levels predict clinical outcomes or that measuring them prevents toxicity is lacking.⁷

A consensus statement from the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists⁷ contains recommendations for monitoring vancomycin therapy, based on a critical evaluation of the available scientific evidence. Their recommendations:

• Vancomycin serum concentrations should be checked to optimize therapy and used as a surrogate marker of effectiveness.
• Trough, rather than peak, levels should be monitored.
• Trough levels should be checked just before the fourth dose, when steady-state levels are likely to have been achieved. More frequent monitoring may be considered in patients with fluctuating renal function.
• Trough levels should be higher than 10 mg/L to prevent the development of resistance.
• To improve antibiotic penetration and optimize the likelihood of achieving pharmacokinetic and pharmacodynamic targets, trough levels of 15 to 20 mg/L are recommended for pathogens with a vancomycin MIC of 1 mg/L or higher and for complicated infections such as endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia.
• For prolonged courses, it is appropriate to check vancomycin levels weekly in hemodynamically stable patients and more often in those who are not hemodynamically stable.

IS VANCOMYCIN NEPHROTOXIC?

In the 1950s, vancomycin formulations were sometimes called “Mississippi mud” because of the many impurities they contained.¹ These impurities were associated with significant nephrotoxicity. Better purification methods used in the manufacture of current formulations mitigate this problem, resulting in a lower incidence of nephrotoxicity.

Over the last several years, organizations such as the American Thoracic Society and the IDSA have recommended targeting higher vancomycin trough concentrations.¹⁰ The consequent widespread use of higher doses has renewed interest in vancomycin’s potential nephrotoxicity.

Lodise et al,¹¹ in a cohort study, examined the incidence of nephrotoxicity with higher daily doses of vancomycin (≥ 4 g/day), lower daily doses (< 4 g/day), and linezolid (Zyvox). They defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/dL or a decrease in calculated creatinine clearance of 50% from baseline on 2 consecutive days.

The incidence of nephrotoxicity was significantly higher in the high-dose vancomycin group (34.6%) than in the low-dose vancomycin group (10.9%) and in the linezolid group (6.7%) (P = .001). Additional factors associated with nephrotoxicity in this study included baseline creatinine clearance less than 86.6 mL/minute, weight greater than 101.4 kg (223.5 lb), and being in an intensive care unit.

Hidayat et al¹² investigated outcomes in patients with high vs low vancomycin trough levels (≥ 15 mg/L vs < 15 mg/L) in a prospective cohort study. Sixty-three patients achieved an average vancomycin trough of 15 to 20 mg/L, and of these, 11 developed nephrotoxicity, compared with no patients in the low-trough group (P = .01). Of the 11 who developed nephrotoxicity, 10 were concomitantly taking other potentially nephrotoxic agents.

Comment. The data on vancomycin and nephrotoxicity are mostly from studies that had limitations such as small numbers of patients, retrospective design, and variable definitions of nephrotoxicity. Many of the patients in these studies had additional factors contributing to nephrotoxicity, including hemodynamic instability and concomitant exposure to other nephrotoxins. Additionally, the sequence of events (nephrotoxicity leading to elevated vancomycin levels vs elevated vancomycin levels causing nephrotoxicity) is still debatable.

The incidence of nephrotoxicity associated with vancomycin therapy is difficult to determine. However, based on current information, the incidence of nephrotoxicity appears to be low when vancomycin is used as monotherapy.

IS S AUREUS BECOMING RESISTANT TO VANCOMYCIN?

An issue of increasing importance in health care settings is the emergence of vancomycin-intermediate S aureus (VISA) and vancomycin-resistant S aureus (VRSA). Eleven cases of VRSA were identified in the United States from 2002 to 2005.¹³ All cases of VRSA in the United States have involved the incorporation of enterococcal vanA cassette into the S aureus genome.¹⁴ While true VRSA isolates remain rare, VISA isolates are becoming more common.

Heteroresistant VISA: An emerging subpopulation of MRSA

Another population of S aureus that has emerged is heteroresistant vancomycin-intermediate S aureus (hVISA). It is defined as the presence of subpopulations of VISA within a population of MRSA at a rate of one organism per 10⁵ to 10⁶ organisms. With traditional testing methods, the vancomycin MIC for the entire population of the strain is within the susceptible range.¹⁵ These hVISA populations are thought to be precursors to the development of VISA.¹⁶

The resistance to vancomycin in hVISA and VISA populations is due to increased cell wall thickness, altered penicillin-binding protein profiles, and decreased cell wall autolysis.

While the true prevalence of hVISA is difficult to predict because of challenges in microbiological detection and probably varies between geographic regions and individual institutions, different studies have reported hVISA rates between 2% and 13% of all MRSA isolates.^15–17

Reduced vancomycin susceptibility can develop regardless of methicillin susceptibility.¹⁸

While hVISA is not common, its presence is thought to be a predictor of failing vancomycin therapy.¹⁵

Factors associated with hVISA bacteremia include high-bacterial-load infections, treatment failure (including persistent bacteremia for more than 7 days), and initially low serum vancomycin levels.¹⁵

 

 

‘MIC creep’: Is it real?

Also worrisome, the average vancomycin MIC for S aureus has been shifting upward, based on reports from several institutions, although it is still within the susceptible range.^19,20 However, this “MIC creep” likely reflects, at least in part, differences in MIC testing and varying methods used to analyze the data.^19,20

Holmes and Jorgensen,²¹ in a single-institution study of MRSA isolates recovered from bacteremic patients from 1999 to 2006, determined that no MIC creep existed when they tested vancomycin MICs using the broth microdilution method. The authors found the MIC₉₀ (ie, the MIC in at least 90% of the isolates) remained less than 1 mg/L during each year of the study.

Sader et al,²² in a multicenter study, evaluated 1,800 MRSA bloodstream isolates from nine hospitals across the United States from 2002 to 2006. Vancomycin MICs were again measured by broth microdilution methods. The mode MIC remained stable at 0.625 mg/L during the study period, and the authors did not detect a trend of rising MICs.

The inconsistency between reports of MIC creep at single institutions and the absence of this phenomenon in large, multicenter studies seems to imply that vancomycin MIC creep is not occurring on a grand scale.

Vancomycin tolerance

Another troubling matter with S aureus and vancomycin is the issue of tolerance. Vancomycin tolerance, defined in terms of increased minimum bactericidal concentration, represents a loss of bactericidal activity. Tolerance to vancomycin can occur even if the MIC remains in the susceptible range.²³

Safdar and Rolston,²⁴ in an observational study from a cancer center, reported that of eight cases of bacteremia that was resistant to vancomycin therapy, three were caused by S aureus.

Sakoulas et al²⁵ found that higher levels of vancomycin bactericidal activity were associated with higher rates of clinical success; however, they found no effect on the mortality rate.

The issue of vancomycin tolerance remains controversial, and because testing for it is impractical in clinical microbiology laboratories, its implications outside the research arena are difficult to ascertain at present.

IS VANCOMYCIN STILL THE BEST DRUG FOR S AUREUS?

MIC break points have been lowered

In 2006, the Clinical Laboratories and Standards Institute lowered its break points for vancomycin MIC categories for S aureus:

• Susceptible: ≤ 2 mg/L (formerly ≤ 4 mg/L)
• Intermediate: 4–8 mg/L (formerly 8–16 mg/L)
• Resistant: ≥ 16 mg/L (formerly ≥ 32 mg/L).

The rationales for these changes were that the lower break points would better detect hVISA, and that cases have been reported of clinical treatment failure of S aureus infections in which the MICs for vancomycin were 4 mg/L.²⁶

Since 2006, the question has been raised whether to lower the break points even further. A reason for this proposal comes from an enhanced understanding of the pharmacokinetics and pharmacodynamics of vancomycin.

The variable most closely associated with clinical response to vancomycin is the AUC-MIC ratio. An AUC-MIC ratio of 400 or higher may be associated with better outcomes in patients with serious S aureus infection. A study of 108 patients with S aureus infection of the lower respiratory tract indicated that organism eradication was more likely if the AUC-MIC ratio was 400 or greater compared with values less than 400, and this was statistically significant.²⁷ However, in cases of S aureus infection with a vancomycin MIC of 2 mg/L or higher, this ratio may not be achievable.

A prospective study of 414 MRSA bacteremia episodes found a vancomycin MIC of 2 mg/L to be a predictor of death.²⁸ The authors concluded that vancomycin may not be the optimal treatment for MRSA with a vancomycin MIC of 2 mg/L.²⁸ Additional studies have also suggested a possible decrease in response to vancomycin in MRSA isolates with elevated MICs within the susceptible range.^25,29

Recent guidelines from the IDSA recommend using the clinical response, regardless of the MIC, to guide antimicrobial selection for isolates with MICs in the susceptible range.²

Combination therapy with vancomycin

As vancomycin use has increased, therapeutic failures with vancomycin have become apparent. Combination therapy has been suggested as an option to increase the efficacy of vancomycin when treating complicated infections.

Rifampin plus vancomycin is controversial.³⁰ The combination is theoretically beneficial, especially in infections associated with prosthetic devices. However, clinical studies have failed to convincingly support its use, and some have suggested that it might prolong bacteremia. In addition, it has numerous drug interactions to consider and adverse effects.³¹

Gentamicin plus vancomycin. The evidence supporting the use of this combination is weak at best. It appears that clinicians may have extrapolated from the success reported by Korzeniowski and Sande,³² who found that methicillin-susceptible S aureus bacteremia was cleared faster if gentamicin was added to nafcillin. A more recent study³³ that compared daptomycin (Cubicin) monotherapy with combined vancomycin and gentamicin to treat MRSA bacteremia and endocarditis showed a better overall success rate with daptomycin (44% vs 32.6%), but the difference was not statistically significant.

Gentamicin has some toxicity. Even short-term use (for the first 4 days of therapy) at low doses for bacteremia and endocarditis due to staphylococci has been associated with a higher rate of renal adverse events, including a significant decrease in creatinine clearance.³⁴

Clindamycin or linezolid plus vancomycin is used to decrease toxin production by S aureus.³⁰

While combination therapy with vancomycin is recommended in specific clinical situations, and the combinations are synergistic in vitro, information is lacking about clinical outcomes to support their use.

 

 

Don’t use vancomycin when another drug would be better

Vancomycin continues to be the drug of choice in many circumstances, but in some instances its role is under scrutiny and another drug might be better.

Beta-lactams. In patients with infection due to methicillin-susceptible S aureus, failure rates are higher with vancomycin than with beta-lactam therapy, specifically nafcillin.^35–37 Beta-lactam antibiotics are thus the drugs of choice for treating infection with beta-lactam-susceptible strains of S aureus.

Linezolid. In theory, linezolid’s ability to decrease production of the S aureus Panton-Valentine leukocidin (PVL) toxin may be an advantage over vancomycin for treating necrotizing pneumonias. For the treatment of MRSA pneumonia, however, controversy exists as to whether linezolid is superior to vancomycin. An analysis of two prospective, randomized, double-blind studies of patients with MRSA pneumonia suggested that initial therapy with linezolid was associated with better survival and clinical cure rates,³⁸ but a subsequent meta-analysis did not substantiate this finding.³⁹ An additional comparative study has been completed, and analysis of the results is in progress.

Daptomycin, approved for skin and soft-tissue infections and bacteremias, including those with right-sided endocarditis, is a lipopeptide antibiotic with a spectrum of action similar to that of vancomycin.⁴⁰ Daptomycin is also active against many strains of vancomycin-resistant enterococci. As noted above, in the MRSA subgroup of the pivotal comparative study of treatment for S aureus bacteremia and endocarditis, the success rate for daptomycin-treated patients (44.4%) was better than that for patients treated with vancomycin plus gentamicin (32.6%), but the difference was not statistically significant.^33,41

The creatine phosphokinase concentration should be monitored weekly in patients on daptomycin.⁴² Daptomycin is inactivated by lung surfactant and should not be used to treat pneumonia.

Other treatment options approved by the US Food and Drug Administration (FDA) for MRSA infections include tigecycline (Tygacil), quinupristin-dalfopristin (Synercid), telavancin (Vibativ), and ceftaroline (Teflaro).

Tigecycline is a glycylcycline with bacteriostatic activity against S aureus and wide distribution to the tissues.⁴³

Quinupristin-dalfopristin, a streptogramin antibiotic, has activity against S aureus. Its use may be associated with severe myalgias, sometimes leading patients to stop taking it.

Telavancin, recently approved by the FDA, is a lipoglycopeptide antibiotic.⁴⁴ It is currently approved to treat complicated skin and skin structure infections and was found to be not inferior to vancomycin. An important side effect of this agent is nephrotoxicity. A negative pregnancy test is required before using this agent in women of childbearing potential.

Ceftaroline, a fifth-generation cephalosporin active against MRSA, has been approved by the FDA for the treatment of skin and skin structure infections and community-acquired pneumonia.⁴⁵

Editor’s note: Portions of this article are based on an article previously published in an internal Cleveland Clinic publication, Pharmacotherapy Update. The version here has been revised, updated, and peer-reviewed.

Acetaminophen (Tylenol, also known as paracetamol, N-acetyl-p-aminophenol, and APAP) is a popular antipyretic and analgesic found in many over-the-counter and prescription products, including cough-and-cold remedies and narcotic pain relievers (Table 1).¹

This drug is generally considered safe, but high doses can be toxic. The number of overdoses is worrisome. In 2006 alone, the American Association of Poison Control Centers implicated acetaminophen in nearly 140,000 poisoning cases, in which more than 100 patients died.² It is responsible for more emergency room visits than any other drug on the market.

According to a position statement from the American Association for the Study of Liver Diseases (AASLD),³ the incidence of acetaminophen-related liver toxicity has been steadily increasing over the past decade, and this drug is now the most common cause of acute liver failure.

MANY OVERDOSES ARE UNINTENTIONAL

Cases of acetaminophen-related liver toxicity can be categorized as either intentional (ie, due to a suicide attempt) or unintentional (ie, due to multiple therapeutic but excessive doses over a period of time, usually more than 3 days).

Up to 50% of cases are unintentional. Bower et al⁴ reviewed cases of acute liver failure that occurred in the Atlanta, GA, area between November 2000 and October 2004. Acetaminophen was the most common cause in adult patients. Of greater concern is that 61% of the acetaminophen-related cases were due to unintentional overdose. According to the Institute for Safe Medication Practices,⁵ one hospital (not named) reported that an average of one patient per day was given more than the recommended maximum daily acetaminophen dose of 4 g while in the hospital.

Many patients take more than one acetaminophen product

Unintentional overdoses or “therapeutic misadventures” are most often due to taking multiple products that contain acetaminophen, taking acetaminophen-narcotic combinations, and impulsive behavior involving a lack of understanding of possible injury in consuming multiple acetaminophen-containing products.³

In the US Food and Drug Administration (FDA) Medwatch Database, in 307 cases of unintentional acetaminophen overdose between 1998 and 2001, 25% of patients had been taking more than one acetaminophencontaining product.⁵

Larson et al⁶ found that one-third of patients who had had an unintentional acetaminophen overdose were taking an acetaminophen-narcotic combination in addition to another acetaminophen-containing product.

Many consumers don’t know they are taking acetaminophen

Many consumers don’t know that some of the drugs they take contain acetaminophen. This may be because many drug labels contain abbreviations for acetaminophen such as “APAP” or have inconsistent formatting that makes it difficult to determine if the product contains acetaminophen.

Others may not be aware of the total maximum recommended daily dose or may not be able to calculate the total daily intake from the information on the label. The problem is not only with over-the-counter products. For example, if a physician prescribes one or two tablets of hydrocodone/acetaminophen (Vicodin) 5 mg/500 mg every 4 to 6 hours, a patient could easily exceed the recommended maximum daily dose of 4 g of acetaminophen.

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

• Chronic alcohol use (ie, more than three drinks per day)
• Malnutrition
• Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

Acetaminophen is an effective antipyretic and analgesic, but its anti-inflammatory properties are minimal, especially compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, acetaminophen is preferred over NSAIDs in some patients because it carries a lower risk of gastrointestinal toxicity (eg, ulceration, bleeding) and so may be better tolerated.¹

INDICATIONS AND DOSAGE

Acetaminophen is indicated for mild to moderate pain or fever, including the pain of osteoarthritis. It is not recommended for chronic inflammatory conditions such as rheumatoid arthritis, since it lacks anti-inflammatory properties.

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

The current package label recommends that the total daily dose not exceed 4 g in most adults. Lower maximum daily doses (eg, 2 g) are recommended in patients who may be at higher risk of hepatotoxicity, such as those who drink heavily, are malnourished, or take enzyme-inducing drugs. Tylenol products currently include an alcohol warning, advising those who consume three or more alcoholic drinks a day to ask their doctor if they should take acetaminophen.

In children up to 12 years of age, the recommended dosage is 10 to 15 mg/kg orally or rectally every 4 to 6 hours. The maximum dosing for children in this age group should not exceed five doses (or 50 to 75 mg/kg) in 24 hours.⁷ In children under age 2 or weighing less than 11 kg, acetaminophen should only be used under the direction of a physician.

 

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

At therapeutic doses, the elimination halflife is about 2 hours. Peak plasma concentrations are reached 30 to 60 minutes after the dose is taken,¹ but taking acetaminophen with opioids, anticholinergic drugs, or even food may delay the time to peak concentration by delaying gastric emptying.⁸

NAPQI is a toxic metabolite

Most of the acetaminophen in the blood undergoes conjugation in the liver with glucuronic acid (40%–67%) and sulfates (20%–46%).⁹ The conjugated metabolites, as well as small amounts that have been hydroxylated and deacetylated, are excreted in the urine (Figure 1).

Under normal circumstances, a small amount of acetaminophen undergoes hepatic metabolism by a different pathway, ie, by CYP450 enzymes, primarily CYP2E1 and to a lesser extent CYP1A2, CYP2A6, and CYP3A4, forming a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Then, the sulfhydryl groups of glutathione convert NAPQI into harmless metabolites that are excreted in the urine.^1,7

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

However, acetaminophen is a dose-dependent hepatotoxin, and excessive doses (intentional or unintentional) may lead to acute liver failure. In addition, even in therapeutic doses, acetaminophen may still cause transient liver enzyme elevations and possibly hepatotoxicity, particularly in people who are malnourished or alcoholic or are taking certain CYP450-inducing drugs.^3,6,10

HOW ACETAMINOPHEN CAN INJURE THE LIVER

Glucuronidation and sulfation, the major metabolic pathways, become saturated after an acetaminophen overdose.⁷ When this happens, more of the toxic metabolite NAPQI is formed by CYP450-mediated N-hydroxylation. When glutathione is depleted after large doses of acetaminophen or in malnourished people, the toxic metabolite accumulates, resulting in liver damage (Figure 1).⁶

The liver is damaged by two mechanisms. In one, NAPQI binds to hepatic cell macromolecules, causing dysfunction of the enzymatic systems, structural and metabolic disarray, and eventually necrotic cell death. The other mechanism is oxidative stress due to depletion of glutathione.

In children, single acetaminophen doses of 120 to 150 mg/kg of body weight have been associated with hepatotoxicity,¹¹ as have single doses of more than 150 mg/kg or a total dose of greater than 7.5 g in adults. However, the minimal dose associated with liver injury has ranged from 4 to 10 g, and in healthy volunteers even therapeutic doses of 1 g orally every 6 hours resulted in mild liver injury.¹²

Patients who are malnourished or fasting are thought to be at greater risk of acetaminophen hepatotoxicity because they may be deficient in glutathione at baseline. In addition, even at lower-than-therapeutic doses, induction of CYP450 enzymes by drugs or chronic alcohol consumption may lead to an increase in the formation of NAPQI, increasing the risk of hepatotoxicity. Examples of drugs that induce CYP450 enzymes to produce more NAPQI include the anticonvuslants phenytoin (Dilantin) and phenobarbital.

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

The diagnosis of acetaminophen overdose is often established by a thorough history. The pertinent information may be difficult to obtain, however, because the patient may be confused or stuporous at presentation, may not know that the overthe-counter products he or she has been taking contain acetaminophen, or may be embarrassed about taking too much acetaminophen.¹³

In acute intentional overdose, signs may not be apparent immediately

The symptoms of toxicity may not be apparent immediately after ingestion of an acute overdose of acetaminophen, but early recognition and treatment can prevent more severe liver damage, decreasing morbidity and the risk of death.⁹

Phase 1 of an acetaminophen overdose begins shortly after ingestion and can last for 12 to 24 hours. Patients may have signs of gastrointestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Although the signs and symptoms show a consistent pattern and are more pronounced after larger acute overdoses, they are not diagnostic or specific.

Phase 2 (up to 48 hours after ingestion). Patients may begin to feel better during this phase. However, the hepatic enzyme levels, the prothrombin time (PT), and the international normalized ratio (INR) may continue to rise, and right upper quadrant pain may develop. Additionally, other laboratory results may be abnormal, and renal insufficiency can occur due to acetaminophen-induced renal tubular necrosis.⁶ Most patients receive the antidote, acetylcysteine (Mycomyst, Acetadote) before or during this phase, and consequently, liver function gradually returns to normal.

Phase 3, if reached, may be marked by severe hepatic necrosis, typically 3 to 5 days after ingestion. Symptoms during this phase range from less severe (eg, nausea and general malaise) to more severe (eg, confusion and stupor). Also, at this time, liver enzyme levels can be as high as 10,000 IU/L or even higher, and lactic acidosis and coagulopathy may worsen. If death should occur, it is most likely from complications associated with fulminant hepatic failure, including cerebral edema, multiorgan-system failure, or sepsis.⁶

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

Many patients who present with unintentional acetaminophen toxicity have been taking the drug or products that contain the drug over several days to treat an acute or chronic medical condition. They often have low or undetectable serum acetaminophen levels after 2 to 3 days of nonspecific symptoms.¹²

 

MANAGING ACETAMINOPHENHEN OVERDOSE

Measuring serum acetaminophen levels may be useful in cases of single, acute overdoses if the time since ingestion is known. The Rumack-Matthew nomogram (Figure 2), used in cases of acute acetaminophen overdose, predicts the probability of hepatotoxicity on the basis of plasma levels and time after ingestion.^13–15

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Acetylcysteine is the antidote for acetaminophen toxicity and should be given within 8 hours of ingestion for maximal protection against hepatic injury in patients whose serum acetaminophen levels are above the “possible” toxicity line on the nomogram.¹⁵ If acetaminophen overdose is suspected but the time elapsed since ingestion cannot be determined, acetylcysteine should be given immediately regardless of the quantity of acetaminophen ingested. ¹⁶ In cases of unintentional overdose, it is often given at the discretion of the physician.

Acetylcysteine limits the toxicity of acetaminophen by increasing glutathione stores, binding with NAPQI as a substitute for glutathione, and enhancing sulfate conjugation.⁶ It may further limit acetaminophen toxicity by nonspecific mechanisms including anti-inflammatory, antioxidant, inotropic, and vasodilating effects.⁶ In addition, it may prevent further hepatic damage in any patient thought to have acetaminophen-related liver toxicity even beyond the first 12 hours of an overdose.¹

Acetylcysteine is available in an oral (Mucomyst) and an intravenous (Acetadote) formulation, which are similar in efficacy. Because many patients find the taste of the oral solution unpleasant and difficult to tolerate, it should be diluted in a 1:3 ratio with cola, orange juice, or other drink to mask its flavor. This mixture should be used within 1 hour of preparation.

Anaphylactoid reactions have occurred in patients receiving intravenous acetylcysteine for acetaminophen overdose soon after the infusion was started, most commonly during the loading dose. The frequency of infusion-related reactions has been reported to be 0.2% to 20.8%.¹⁵

The recommended dosage for intravenous acetylcysteine is a loading dose of 150 mg/kg given over 60 minutes, followed by a second dose of 50 mg/kg given over 4 hours, and finally a third dose of 100 mg/kg given over 16 hours.¹⁵ For oral acetylcysteine, the loading dose is 140 mg/kg followed by 70 mg/kg every 4 hours for 17 additional doses.¹⁷

Other measures

Activated charcoal can be used if the patient presents within 1 to 2 hours after taking acetaminophen. However, the rapid gastrointestinal absorption of acetaminophen makes this treatment ineffective in most cases.⁹

Liver transplantation. In patients with acute liver failure and a poor prognosis, early referral to a liver transplant center is essential. The King’s College criteria (Table 2),¹⁸ a widely used prognostic model in patients with acute liver failure, are used to predict the need for liver transplantation. They are based on the arterial pH, the PT and INR, the severity of encephalopathy, and the serum creatinine concentration.

FINDINGS FROM LARGE REGISTRIES

Findings in adults

Ostapowicz et al,¹⁹ as part of the Acute Liver Failure Study Group, in 2002 prospectively characterized the short-term outcomes of acute liver failure in a large number of patients at 17 tertiary care centers in the United States over approximately 41 months. All centers except one performed liver transplants. Eligible patients had to meet criteria for acute liver failure, including an INR higher than 1.5, evidence of hepatic encephalopathy, and presentation within 26 weeks of illness onset without apparent chronic liver disease.

Of the 308 cases of acute liver failure, 120 (39%) were from acetaminophen overdose, making this drug the most common cause of acute liver failure. Forty-four (37%) of the patients with acetaminophen-related acute liver failure were trying to commit suicide, 57% of cases were accidental, and the remaining reasons for acetaminophen overdose were unknown. The median amount ingested was 13.2 g/day (range 2.6–75 g), and 99 (83%) of the 120 patients took more than 4 g/day.

The patients with acetaminophen-related acute liver toxicity differed from those with other causes of acute liver failure such as idiosyncratic drug reactions or indeterminate causes. The acetaminophen group had a shorter duration of disease and higher serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine than those with acute liver failure from other causes. They also had lower bilirubin levels and a lower arterial pH.

Rates of liver transplantation were 6% in the acetaminophen group, 53% in the group with other drug-induced liver toxicity, 51% in the indeterminate group, and 36% in the remaining groups. Of the acetaminophen group, 47% met the criteria for transplantation, but only 57% of those eligible were listed for transplantation. Those excluded from the transplant list had medical contraindications or were excluded for psychosocial reasons. The short-term transplant-free survival rate was 68% in the acetaminophen group.

Overall, 11% of the patients died, including 28% of the acetaminophen group. The authors concluded that most cases of liver injury in the United States are due to medications and may be preventable.

Larson et al,²⁰ as part of the Acute Liver Failure Study Group, examined the incidence, risk factors, and outcomes of acetaminopheninduced acute liver failure at 22 tertiary care centers in the United States over a 6-year period. Of the 662 patients in the study, 302 had acetaminophen-related toxicity and 275 were included in the final analysis; some of them had been included in the study by Ostapowicz et al.¹⁹ During the study period, the number of cases of acute liver toxicity related to acetaminophen increased from 28% to 51%.

Of the patients enrolled in the study, 56% met the criteria for potentially toxic acetaminophen ingestion. Of those who met the criteria, 77% had detectable acetaminophen levels in their serum, and 91% had ALT levels higher than 1,000 IU/L. The time between ingestion and symptom onset ranged from 1 to 32 days, and the median dose was 24 g (range 1.2–180 g).

Of the overdose cases, 48% were unintentional, 44% were intentional, and the remaining 8% had no definable reason. Of the patients in the unintentional-overdose group, 38% were using more than one acetaminophen-containing product and 63% were taking combination products containing narcotics. Overeall, 44% of patients reported using narcotic-acetaminophen combination products. The unintentional-overdose group had lower serum acetaminophen levels than the intentional-overdose group, but they were more likely to present with severe hepatic encephalopathy.

The number of patients with an unintentional overdose was worrisome. Furthermore, one-third of the patients who were receiving an acetaminophen-narcotic combination product were taking an additional acetaminophencontaining product. The authors concluded that unintentional overdose is the leading cause of acetaminophen-related hepatotoxicity, and efforts to limit the over-the-counter package size and to restrict prescriptions of acetaminophen-narcotic combinations may be necessary to decrease the incidence of this preventable cause of acute liver failure.

 

 

Findings in children

Squires et al²¹ and the Pediatric Acute Liver Failure Study Group examined the pathogenesis, treatment, and outcome of acute liver failure in children (any age from birth to 18 years) with no previous evidence of chronic liver disease, evidence of acute liver injury, or hepatic-based coagulopathy. From December 1999 to December 2004, 348 patients were enrolled.

Fourteen percent of the cases were due to acetaminophen. The median dose of acetaminophen ingested was 183 mg/kg. Most of these patients were white and female, and 96% were over age 3. Hepatic encephalopathy was more common in the non-acetaminophen groups than in the acetaminophen group, although this is often difficult to assess in infants and children. Children with acetaminophen toxicity had the highest rate of spontaneous recovery: 45 (94%) of 48 recovered.

Although there are fewer acetaminophenrelated cases of acute liver failure in children than in adults, the use of acetaminophen in children is still worrisome. The authors concluded that if they do not have hepatic encephalopathy, children with acetaminopheninduced liver toxicity have an excellent prognosis.

THE FDA LOOKS AT THE PROBLEM

Why overdoses occur

A recent FDA report²² cited the following reasons for acetaminophen overdose:

• Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
• Some patients may be more prone to liver injury from acetaminophen.
• The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
• Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
• Consumers are unaware of the risk of liver toxicity with acetaminophen.
• Prescription products are not always clearly labeled with acetaminophen as an ingredient.
• Pediatric dosage forms are available in many different concentrations.

New package labeling

In view of this information, the FDA has mandated new labeling for acetaminophencontaining products (Table 3).²²

Recommendations from an advisory panel

In addition, an FDA advisory panel recommended decreasing the maximum recommended daily dose (possibly to 3,250 mg/day in adults, although this is not final) to help prevent overdoses, and reducing the maximum amount in a single nonprescription dose of the drug to 650 mg.²³ The panel also voted (by a narrow margin) to ban all acetaminophen-narcotic combination products.

As of this writing, the FDA has not adopted these recommendations. (Although the FDA is not obliged to follow the advice of its advisory panels, in most cases it does.) The recommendations about acetaminophen could take years to implement fully.

THE UNITED KINGDOM ACTED IN 1998

In response to a rising number of analgesicrelated deaths, the United Kingdom enacted legislation in 1998 to limit the package size available to consumers.²⁴ Packages sold in general stores can contain no more than 16 capsules, while those sold in pharmacies can contain 24. Blister packs were also introduced to make it harder for people to impulsively take handfuls of tablets.²⁵

Two studies since then both found that the number of deaths related to paracetamol (as acetaminophen is known in the United Kingdom) had fallen since the legislation was implemented.^24,26 Greene et al²⁷ found that patients who ingested potentially toxic doses of paracetamol had obtained the drug “in a manner contravening the 1998 legislation.”²⁷ In other words, shops in London were not obeying the law.

SUMMARY

The new labeling and the proposed changes are sensible and draw needed attention to the problem of acetaminophen toxicity. To prevent unintentional acetaminophen overdoses, education of patients and health care professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.

Editor’s note: Portions of this article are based on an article previously published in an internal Cleveland Clinic publication, Pharmacotherapy Update. The version here has been revised, updated, and peer-reviewed.

Acetaminophen (Tylenol, also known as paracetamol, N-acetyl-p-aminophenol, and APAP) is a popular antipyretic and analgesic found in many over-the-counter and prescription products, including cough-and-cold remedies and narcotic pain relievers (Table 1).¹

This drug is generally considered safe, but high doses can be toxic. The number of overdoses is worrisome. In 2006 alone, the American Association of Poison Control Centers implicated acetaminophen in nearly 140,000 poisoning cases, in which more than 100 patients died.² It is responsible for more emergency room visits than any other drug on the market.

According to a position statement from the American Association for the Study of Liver Diseases (AASLD),³ the incidence of acetaminophen-related liver toxicity has been steadily increasing over the past decade, and this drug is now the most common cause of acute liver failure.

MANY OVERDOSES ARE UNINTENTIONAL

Cases of acetaminophen-related liver toxicity can be categorized as either intentional (ie, due to a suicide attempt) or unintentional (ie, due to multiple therapeutic but excessive doses over a period of time, usually more than 3 days).

Up to 50% of cases are unintentional. Bower et al⁴ reviewed cases of acute liver failure that occurred in the Atlanta, GA, area between November 2000 and October 2004. Acetaminophen was the most common cause in adult patients. Of greater concern is that 61% of the acetaminophen-related cases were due to unintentional overdose. According to the Institute for Safe Medication Practices,⁵ one hospital (not named) reported that an average of one patient per day was given more than the recommended maximum daily acetaminophen dose of 4 g while in the hospital.

Many patients take more than one acetaminophen product

Unintentional overdoses or “therapeutic misadventures” are most often due to taking multiple products that contain acetaminophen, taking acetaminophen-narcotic combinations, and impulsive behavior involving a lack of understanding of possible injury in consuming multiple acetaminophen-containing products.³

In the US Food and Drug Administration (FDA) Medwatch Database, in 307 cases of unintentional acetaminophen overdose between 1998 and 2001, 25% of patients had been taking more than one acetaminophencontaining product.⁵

Larson et al⁶ found that one-third of patients who had had an unintentional acetaminophen overdose were taking an acetaminophen-narcotic combination in addition to another acetaminophen-containing product.

Many consumers don’t know they are taking acetaminophen

Many consumers don’t know that some of the drugs they take contain acetaminophen. This may be because many drug labels contain abbreviations for acetaminophen such as “APAP” or have inconsistent formatting that makes it difficult to determine if the product contains acetaminophen.

Others may not be aware of the total maximum recommended daily dose or may not be able to calculate the total daily intake from the information on the label. The problem is not only with over-the-counter products. For example, if a physician prescribes one or two tablets of hydrocodone/acetaminophen (Vicodin) 5 mg/500 mg every 4 to 6 hours, a patient could easily exceed the recommended maximum daily dose of 4 g of acetaminophen.

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

• Chronic alcohol use (ie, more than three drinks per day)
• Malnutrition
• Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

Acetaminophen is an effective antipyretic and analgesic, but its anti-inflammatory properties are minimal, especially compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, acetaminophen is preferred over NSAIDs in some patients because it carries a lower risk of gastrointestinal toxicity (eg, ulceration, bleeding) and so may be better tolerated.¹

INDICATIONS AND DOSAGE

Acetaminophen is indicated for mild to moderate pain or fever, including the pain of osteoarthritis. It is not recommended for chronic inflammatory conditions such as rheumatoid arthritis, since it lacks anti-inflammatory properties.

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

The current package label recommends that the total daily dose not exceed 4 g in most adults. Lower maximum daily doses (eg, 2 g) are recommended in patients who may be at higher risk of hepatotoxicity, such as those who drink heavily, are malnourished, or take enzyme-inducing drugs. Tylenol products currently include an alcohol warning, advising those who consume three or more alcoholic drinks a day to ask their doctor if they should take acetaminophen.

In children up to 12 years of age, the recommended dosage is 10 to 15 mg/kg orally or rectally every 4 to 6 hours. The maximum dosing for children in this age group should not exceed five doses (or 50 to 75 mg/kg) in 24 hours.⁷ In children under age 2 or weighing less than 11 kg, acetaminophen should only be used under the direction of a physician.

 

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

At therapeutic doses, the elimination halflife is about 2 hours. Peak plasma concentrations are reached 30 to 60 minutes after the dose is taken,¹ but taking acetaminophen with opioids, anticholinergic drugs, or even food may delay the time to peak concentration by delaying gastric emptying.⁸

NAPQI is a toxic metabolite

Most of the acetaminophen in the blood undergoes conjugation in the liver with glucuronic acid (40%–67%) and sulfates (20%–46%).⁹ The conjugated metabolites, as well as small amounts that have been hydroxylated and deacetylated, are excreted in the urine (Figure 1).

Under normal circumstances, a small amount of acetaminophen undergoes hepatic metabolism by a different pathway, ie, by CYP450 enzymes, primarily CYP2E1 and to a lesser extent CYP1A2, CYP2A6, and CYP3A4, forming a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Then, the sulfhydryl groups of glutathione convert NAPQI into harmless metabolites that are excreted in the urine.^1,7

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

However, acetaminophen is a dose-dependent hepatotoxin, and excessive doses (intentional or unintentional) may lead to acute liver failure. In addition, even in therapeutic doses, acetaminophen may still cause transient liver enzyme elevations and possibly hepatotoxicity, particularly in people who are malnourished or alcoholic or are taking certain CYP450-inducing drugs.^3,6,10

HOW ACETAMINOPHEN CAN INJURE THE LIVER

Glucuronidation and sulfation, the major metabolic pathways, become saturated after an acetaminophen overdose.⁷ When this happens, more of the toxic metabolite NAPQI is formed by CYP450-mediated N-hydroxylation. When glutathione is depleted after large doses of acetaminophen or in malnourished people, the toxic metabolite accumulates, resulting in liver damage (Figure 1).⁶

The liver is damaged by two mechanisms. In one, NAPQI binds to hepatic cell macromolecules, causing dysfunction of the enzymatic systems, structural and metabolic disarray, and eventually necrotic cell death. The other mechanism is oxidative stress due to depletion of glutathione.

In children, single acetaminophen doses of 120 to 150 mg/kg of body weight have been associated with hepatotoxicity,¹¹ as have single doses of more than 150 mg/kg or a total dose of greater than 7.5 g in adults. However, the minimal dose associated with liver injury has ranged from 4 to 10 g, and in healthy volunteers even therapeutic doses of 1 g orally every 6 hours resulted in mild liver injury.¹²

Patients who are malnourished or fasting are thought to be at greater risk of acetaminophen hepatotoxicity because they may be deficient in glutathione at baseline. In addition, even at lower-than-therapeutic doses, induction of CYP450 enzymes by drugs or chronic alcohol consumption may lead to an increase in the formation of NAPQI, increasing the risk of hepatotoxicity. Examples of drugs that induce CYP450 enzymes to produce more NAPQI include the anticonvuslants phenytoin (Dilantin) and phenobarbital.

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

The diagnosis of acetaminophen overdose is often established by a thorough history. The pertinent information may be difficult to obtain, however, because the patient may be confused or stuporous at presentation, may not know that the overthe-counter products he or she has been taking contain acetaminophen, or may be embarrassed about taking too much acetaminophen.¹³

In acute intentional overdose, signs may not be apparent immediately

The symptoms of toxicity may not be apparent immediately after ingestion of an acute overdose of acetaminophen, but early recognition and treatment can prevent more severe liver damage, decreasing morbidity and the risk of death.⁹

Phase 1 of an acetaminophen overdose begins shortly after ingestion and can last for 12 to 24 hours. Patients may have signs of gastrointestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Although the signs and symptoms show a consistent pattern and are more pronounced after larger acute overdoses, they are not diagnostic or specific.

Phase 2 (up to 48 hours after ingestion). Patients may begin to feel better during this phase. However, the hepatic enzyme levels, the prothrombin time (PT), and the international normalized ratio (INR) may continue to rise, and right upper quadrant pain may develop. Additionally, other laboratory results may be abnormal, and renal insufficiency can occur due to acetaminophen-induced renal tubular necrosis.⁶ Most patients receive the antidote, acetylcysteine (Mycomyst, Acetadote) before or during this phase, and consequently, liver function gradually returns to normal.

Phase 3, if reached, may be marked by severe hepatic necrosis, typically 3 to 5 days after ingestion. Symptoms during this phase range from less severe (eg, nausea and general malaise) to more severe (eg, confusion and stupor). Also, at this time, liver enzyme levels can be as high as 10,000 IU/L or even higher, and lactic acidosis and coagulopathy may worsen. If death should occur, it is most likely from complications associated with fulminant hepatic failure, including cerebral edema, multiorgan-system failure, or sepsis.⁶

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

Many patients who present with unintentional acetaminophen toxicity have been taking the drug or products that contain the drug over several days to treat an acute or chronic medical condition. They often have low or undetectable serum acetaminophen levels after 2 to 3 days of nonspecific symptoms.¹²

 

MANAGING ACETAMINOPHENHEN OVERDOSE

Measuring serum acetaminophen levels may be useful in cases of single, acute overdoses if the time since ingestion is known. The Rumack-Matthew nomogram (Figure 2), used in cases of acute acetaminophen overdose, predicts the probability of hepatotoxicity on the basis of plasma levels and time after ingestion.^13–15

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Acetylcysteine is the antidote for acetaminophen toxicity and should be given within 8 hours of ingestion for maximal protection against hepatic injury in patients whose serum acetaminophen levels are above the “possible” toxicity line on the nomogram.¹⁵ If acetaminophen overdose is suspected but the time elapsed since ingestion cannot be determined, acetylcysteine should be given immediately regardless of the quantity of acetaminophen ingested. ¹⁶ In cases of unintentional overdose, it is often given at the discretion of the physician.

Acetylcysteine limits the toxicity of acetaminophen by increasing glutathione stores, binding with NAPQI as a substitute for glutathione, and enhancing sulfate conjugation.⁶ It may further limit acetaminophen toxicity by nonspecific mechanisms including anti-inflammatory, antioxidant, inotropic, and vasodilating effects.⁶ In addition, it may prevent further hepatic damage in any patient thought to have acetaminophen-related liver toxicity even beyond the first 12 hours of an overdose.¹

Acetylcysteine is available in an oral (Mucomyst) and an intravenous (Acetadote) formulation, which are similar in efficacy. Because many patients find the taste of the oral solution unpleasant and difficult to tolerate, it should be diluted in a 1:3 ratio with cola, orange juice, or other drink to mask its flavor. This mixture should be used within 1 hour of preparation.

Anaphylactoid reactions have occurred in patients receiving intravenous acetylcysteine for acetaminophen overdose soon after the infusion was started, most commonly during the loading dose. The frequency of infusion-related reactions has been reported to be 0.2% to 20.8%.¹⁵

The recommended dosage for intravenous acetylcysteine is a loading dose of 150 mg/kg given over 60 minutes, followed by a second dose of 50 mg/kg given over 4 hours, and finally a third dose of 100 mg/kg given over 16 hours.¹⁵ For oral acetylcysteine, the loading dose is 140 mg/kg followed by 70 mg/kg every 4 hours for 17 additional doses.¹⁷

Other measures

Activated charcoal can be used if the patient presents within 1 to 2 hours after taking acetaminophen. However, the rapid gastrointestinal absorption of acetaminophen makes this treatment ineffective in most cases.⁹

Liver transplantation. In patients with acute liver failure and a poor prognosis, early referral to a liver transplant center is essential. The King’s College criteria (Table 2),¹⁸ a widely used prognostic model in patients with acute liver failure, are used to predict the need for liver transplantation. They are based on the arterial pH, the PT and INR, the severity of encephalopathy, and the serum creatinine concentration.

FINDINGS FROM LARGE REGISTRIES

Findings in adults

Ostapowicz et al,¹⁹ as part of the Acute Liver Failure Study Group, in 2002 prospectively characterized the short-term outcomes of acute liver failure in a large number of patients at 17 tertiary care centers in the United States over approximately 41 months. All centers except one performed liver transplants. Eligible patients had to meet criteria for acute liver failure, including an INR higher than 1.5, evidence of hepatic encephalopathy, and presentation within 26 weeks of illness onset without apparent chronic liver disease.

Of the 308 cases of acute liver failure, 120 (39%) were from acetaminophen overdose, making this drug the most common cause of acute liver failure. Forty-four (37%) of the patients with acetaminophen-related acute liver failure were trying to commit suicide, 57% of cases were accidental, and the remaining reasons for acetaminophen overdose were unknown. The median amount ingested was 13.2 g/day (range 2.6–75 g), and 99 (83%) of the 120 patients took more than 4 g/day.

The patients with acetaminophen-related acute liver toxicity differed from those with other causes of acute liver failure such as idiosyncratic drug reactions or indeterminate causes. The acetaminophen group had a shorter duration of disease and higher serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine than those with acute liver failure from other causes. They also had lower bilirubin levels and a lower arterial pH.

Rates of liver transplantation were 6% in the acetaminophen group, 53% in the group with other drug-induced liver toxicity, 51% in the indeterminate group, and 36% in the remaining groups. Of the acetaminophen group, 47% met the criteria for transplantation, but only 57% of those eligible were listed for transplantation. Those excluded from the transplant list had medical contraindications or were excluded for psychosocial reasons. The short-term transplant-free survival rate was 68% in the acetaminophen group.

Overall, 11% of the patients died, including 28% of the acetaminophen group. The authors concluded that most cases of liver injury in the United States are due to medications and may be preventable.

Larson et al,²⁰ as part of the Acute Liver Failure Study Group, examined the incidence, risk factors, and outcomes of acetaminopheninduced acute liver failure at 22 tertiary care centers in the United States over a 6-year period. Of the 662 patients in the study, 302 had acetaminophen-related toxicity and 275 were included in the final analysis; some of them had been included in the study by Ostapowicz et al.¹⁹ During the study period, the number of cases of acute liver toxicity related to acetaminophen increased from 28% to 51%.

Of the patients enrolled in the study, 56% met the criteria for potentially toxic acetaminophen ingestion. Of those who met the criteria, 77% had detectable acetaminophen levels in their serum, and 91% had ALT levels higher than 1,000 IU/L. The time between ingestion and symptom onset ranged from 1 to 32 days, and the median dose was 24 g (range 1.2–180 g).

Of the overdose cases, 48% were unintentional, 44% were intentional, and the remaining 8% had no definable reason. Of the patients in the unintentional-overdose group, 38% were using more than one acetaminophen-containing product and 63% were taking combination products containing narcotics. Overeall, 44% of patients reported using narcotic-acetaminophen combination products. The unintentional-overdose group had lower serum acetaminophen levels than the intentional-overdose group, but they were more likely to present with severe hepatic encephalopathy.

The number of patients with an unintentional overdose was worrisome. Furthermore, one-third of the patients who were receiving an acetaminophen-narcotic combination product were taking an additional acetaminophencontaining product. The authors concluded that unintentional overdose is the leading cause of acetaminophen-related hepatotoxicity, and efforts to limit the over-the-counter package size and to restrict prescriptions of acetaminophen-narcotic combinations may be necessary to decrease the incidence of this preventable cause of acute liver failure.

 

 

Findings in children

Squires et al²¹ and the Pediatric Acute Liver Failure Study Group examined the pathogenesis, treatment, and outcome of acute liver failure in children (any age from birth to 18 years) with no previous evidence of chronic liver disease, evidence of acute liver injury, or hepatic-based coagulopathy. From December 1999 to December 2004, 348 patients were enrolled.

Fourteen percent of the cases were due to acetaminophen. The median dose of acetaminophen ingested was 183 mg/kg. Most of these patients were white and female, and 96% were over age 3. Hepatic encephalopathy was more common in the non-acetaminophen groups than in the acetaminophen group, although this is often difficult to assess in infants and children. Children with acetaminophen toxicity had the highest rate of spontaneous recovery: 45 (94%) of 48 recovered.

Although there are fewer acetaminophenrelated cases of acute liver failure in children than in adults, the use of acetaminophen in children is still worrisome. The authors concluded that if they do not have hepatic encephalopathy, children with acetaminopheninduced liver toxicity have an excellent prognosis.

THE FDA LOOKS AT THE PROBLEM

Why overdoses occur

A recent FDA report²² cited the following reasons for acetaminophen overdose:

• Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
• Some patients may be more prone to liver injury from acetaminophen.
• The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
• Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
• Consumers are unaware of the risk of liver toxicity with acetaminophen.
• Prescription products are not always clearly labeled with acetaminophen as an ingredient.
• Pediatric dosage forms are available in many different concentrations.

New package labeling

In view of this information, the FDA has mandated new labeling for acetaminophencontaining products (Table 3).²²

Recommendations from an advisory panel

In addition, an FDA advisory panel recommended decreasing the maximum recommended daily dose (possibly to 3,250 mg/day in adults, although this is not final) to help prevent overdoses, and reducing the maximum amount in a single nonprescription dose of the drug to 650 mg.²³ The panel also voted (by a narrow margin) to ban all acetaminophen-narcotic combination products.

As of this writing, the FDA has not adopted these recommendations. (Although the FDA is not obliged to follow the advice of its advisory panels, in most cases it does.) The recommendations about acetaminophen could take years to implement fully.

THE UNITED KINGDOM ACTED IN 1998

In response to a rising number of analgesicrelated deaths, the United Kingdom enacted legislation in 1998 to limit the package size available to consumers.²⁴ Packages sold in general stores can contain no more than 16 capsules, while those sold in pharmacies can contain 24. Blister packs were also introduced to make it harder for people to impulsively take handfuls of tablets.²⁵

Two studies since then both found that the number of deaths related to paracetamol (as acetaminophen is known in the United Kingdom) had fallen since the legislation was implemented.^24,26 Greene et al²⁷ found that patients who ingested potentially toxic doses of paracetamol had obtained the drug “in a manner contravening the 1998 legislation.”²⁷ In other words, shops in London were not obeying the law.

SUMMARY

The new labeling and the proposed changes are sensible and draw needed attention to the problem of acetaminophen toxicity. To prevent unintentional acetaminophen overdoses, education of patients and health care professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.

Editor’s note: Portions of this article are based on an article previously published in an internal Cleveland Clinic publication, Pharmacotherapy Update. The version here has been revised, updated, and peer-reviewed.

Acetaminophen (Tylenol, also known as paracetamol, N-acetyl-p-aminophenol, and APAP) is a popular antipyretic and analgesic found in many over-the-counter and prescription products, including cough-and-cold remedies and narcotic pain relievers (Table 1).¹

This drug is generally considered safe, but high doses can be toxic. The number of overdoses is worrisome. In 2006 alone, the American Association of Poison Control Centers implicated acetaminophen in nearly 140,000 poisoning cases, in which more than 100 patients died.² It is responsible for more emergency room visits than any other drug on the market.

According to a position statement from the American Association for the Study of Liver Diseases (AASLD),³ the incidence of acetaminophen-related liver toxicity has been steadily increasing over the past decade, and this drug is now the most common cause of acute liver failure.

MANY OVERDOSES ARE UNINTENTIONAL

Cases of acetaminophen-related liver toxicity can be categorized as either intentional (ie, due to a suicide attempt) or unintentional (ie, due to multiple therapeutic but excessive doses over a period of time, usually more than 3 days).

Up to 50% of cases are unintentional. Bower et al⁴ reviewed cases of acute liver failure that occurred in the Atlanta, GA, area between November 2000 and October 2004. Acetaminophen was the most common cause in adult patients. Of greater concern is that 61% of the acetaminophen-related cases were due to unintentional overdose. According to the Institute for Safe Medication Practices,⁵ one hospital (not named) reported that an average of one patient per day was given more than the recommended maximum daily acetaminophen dose of 4 g while in the hospital.

Many patients take more than one acetaminophen product

Unintentional overdoses or “therapeutic misadventures” are most often due to taking multiple products that contain acetaminophen, taking acetaminophen-narcotic combinations, and impulsive behavior involving a lack of understanding of possible injury in consuming multiple acetaminophen-containing products.³

In the US Food and Drug Administration (FDA) Medwatch Database, in 307 cases of unintentional acetaminophen overdose between 1998 and 2001, 25% of patients had been taking more than one acetaminophencontaining product.⁵

Larson et al⁶ found that one-third of patients who had had an unintentional acetaminophen overdose were taking an acetaminophen-narcotic combination in addition to another acetaminophen-containing product.

Many consumers don’t know they are taking acetaminophen

Many consumers don’t know that some of the drugs they take contain acetaminophen. This may be because many drug labels contain abbreviations for acetaminophen such as “APAP” or have inconsistent formatting that makes it difficult to determine if the product contains acetaminophen.

Others may not be aware of the total maximum recommended daily dose or may not be able to calculate the total daily intake from the information on the label. The problem is not only with over-the-counter products. For example, if a physician prescribes one or two tablets of hydrocodone/acetaminophen (Vicodin) 5 mg/500 mg every 4 to 6 hours, a patient could easily exceed the recommended maximum daily dose of 4 g of acetaminophen.

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

• Chronic alcohol use (ie, more than three drinks per day)
• Malnutrition
• Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

Acetaminophen is an effective antipyretic and analgesic, but its anti-inflammatory properties are minimal, especially compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, acetaminophen is preferred over NSAIDs in some patients because it carries a lower risk of gastrointestinal toxicity (eg, ulceration, bleeding) and so may be better tolerated.¹

INDICATIONS AND DOSAGE

Acetaminophen is indicated for mild to moderate pain or fever, including the pain of osteoarthritis. It is not recommended for chronic inflammatory conditions such as rheumatoid arthritis, since it lacks anti-inflammatory properties.

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

The current package label recommends that the total daily dose not exceed 4 g in most adults. Lower maximum daily doses (eg, 2 g) are recommended in patients who may be at higher risk of hepatotoxicity, such as those who drink heavily, are malnourished, or take enzyme-inducing drugs. Tylenol products currently include an alcohol warning, advising those who consume three or more alcoholic drinks a day to ask their doctor if they should take acetaminophen.

In children up to 12 years of age, the recommended dosage is 10 to 15 mg/kg orally or rectally every 4 to 6 hours. The maximum dosing for children in this age group should not exceed five doses (or 50 to 75 mg/kg) in 24 hours.⁷ In children under age 2 or weighing less than 11 kg, acetaminophen should only be used under the direction of a physician.

 

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

At therapeutic doses, the elimination halflife is about 2 hours. Peak plasma concentrations are reached 30 to 60 minutes after the dose is taken,¹ but taking acetaminophen with opioids, anticholinergic drugs, or even food may delay the time to peak concentration by delaying gastric emptying.⁸

NAPQI is a toxic metabolite

Most of the acetaminophen in the blood undergoes conjugation in the liver with glucuronic acid (40%–67%) and sulfates (20%–46%).⁹ The conjugated metabolites, as well as small amounts that have been hydroxylated and deacetylated, are excreted in the urine (Figure 1).

Under normal circumstances, a small amount of acetaminophen undergoes hepatic metabolism by a different pathway, ie, by CYP450 enzymes, primarily CYP2E1 and to a lesser extent CYP1A2, CYP2A6, and CYP3A4, forming a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Then, the sulfhydryl groups of glutathione convert NAPQI into harmless metabolites that are excreted in the urine.^1,7

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

However, acetaminophen is a dose-dependent hepatotoxin, and excessive doses (intentional or unintentional) may lead to acute liver failure. In addition, even in therapeutic doses, acetaminophen may still cause transient liver enzyme elevations and possibly hepatotoxicity, particularly in people who are malnourished or alcoholic or are taking certain CYP450-inducing drugs.^3,6,10

HOW ACETAMINOPHEN CAN INJURE THE LIVER

Glucuronidation and sulfation, the major metabolic pathways, become saturated after an acetaminophen overdose.⁷ When this happens, more of the toxic metabolite NAPQI is formed by CYP450-mediated N-hydroxylation. When glutathione is depleted after large doses of acetaminophen or in malnourished people, the toxic metabolite accumulates, resulting in liver damage (Figure 1).⁶

The liver is damaged by two mechanisms. In one, NAPQI binds to hepatic cell macromolecules, causing dysfunction of the enzymatic systems, structural and metabolic disarray, and eventually necrotic cell death. The other mechanism is oxidative stress due to depletion of glutathione.

In children, single acetaminophen doses of 120 to 150 mg/kg of body weight have been associated with hepatotoxicity,¹¹ as have single doses of more than 150 mg/kg or a total dose of greater than 7.5 g in adults. However, the minimal dose associated with liver injury has ranged from 4 to 10 g, and in healthy volunteers even therapeutic doses of 1 g orally every 6 hours resulted in mild liver injury.¹²

Patients who are malnourished or fasting are thought to be at greater risk of acetaminophen hepatotoxicity because they may be deficient in glutathione at baseline. In addition, even at lower-than-therapeutic doses, induction of CYP450 enzymes by drugs or chronic alcohol consumption may lead to an increase in the formation of NAPQI, increasing the risk of hepatotoxicity. Examples of drugs that induce CYP450 enzymes to produce more NAPQI include the anticonvuslants phenytoin (Dilantin) and phenobarbital.

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

The diagnosis of acetaminophen overdose is often established by a thorough history. The pertinent information may be difficult to obtain, however, because the patient may be confused or stuporous at presentation, may not know that the overthe-counter products he or she has been taking contain acetaminophen, or may be embarrassed about taking too much acetaminophen.¹³

In acute intentional overdose, signs may not be apparent immediately

The symptoms of toxicity may not be apparent immediately after ingestion of an acute overdose of acetaminophen, but early recognition and treatment can prevent more severe liver damage, decreasing morbidity and the risk of death.⁹

Phase 1 of an acetaminophen overdose begins shortly after ingestion and can last for 12 to 24 hours. Patients may have signs of gastrointestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Although the signs and symptoms show a consistent pattern and are more pronounced after larger acute overdoses, they are not diagnostic or specific.

Phase 2 (up to 48 hours after ingestion). Patients may begin to feel better during this phase. However, the hepatic enzyme levels, the prothrombin time (PT), and the international normalized ratio (INR) may continue to rise, and right upper quadrant pain may develop. Additionally, other laboratory results may be abnormal, and renal insufficiency can occur due to acetaminophen-induced renal tubular necrosis.⁶ Most patients receive the antidote, acetylcysteine (Mycomyst, Acetadote) before or during this phase, and consequently, liver function gradually returns to normal.

Phase 3, if reached, may be marked by severe hepatic necrosis, typically 3 to 5 days after ingestion. Symptoms during this phase range from less severe (eg, nausea and general malaise) to more severe (eg, confusion and stupor). Also, at this time, liver enzyme levels can be as high as 10,000 IU/L or even higher, and lactic acidosis and coagulopathy may worsen. If death should occur, it is most likely from complications associated with fulminant hepatic failure, including cerebral edema, multiorgan-system failure, or sepsis.⁶

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

Many patients who present with unintentional acetaminophen toxicity have been taking the drug or products that contain the drug over several days to treat an acute or chronic medical condition. They often have low or undetectable serum acetaminophen levels after 2 to 3 days of nonspecific symptoms.¹²

 

MANAGING ACETAMINOPHENHEN OVERDOSE

Measuring serum acetaminophen levels may be useful in cases of single, acute overdoses if the time since ingestion is known. The Rumack-Matthew nomogram (Figure 2), used in cases of acute acetaminophen overdose, predicts the probability of hepatotoxicity on the basis of plasma levels and time after ingestion.^13–15

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Acetylcysteine is the antidote for acetaminophen toxicity and should be given within 8 hours of ingestion for maximal protection against hepatic injury in patients whose serum acetaminophen levels are above the “possible” toxicity line on the nomogram.¹⁵ If acetaminophen overdose is suspected but the time elapsed since ingestion cannot be determined, acetylcysteine should be given immediately regardless of the quantity of acetaminophen ingested. ¹⁶ In cases of unintentional overdose, it is often given at the discretion of the physician.

Acetylcysteine limits the toxicity of acetaminophen by increasing glutathione stores, binding with NAPQI as a substitute for glutathione, and enhancing sulfate conjugation.⁶ It may further limit acetaminophen toxicity by nonspecific mechanisms including anti-inflammatory, antioxidant, inotropic, and vasodilating effects.⁶ In addition, it may prevent further hepatic damage in any patient thought to have acetaminophen-related liver toxicity even beyond the first 12 hours of an overdose.¹

Acetylcysteine is available in an oral (Mucomyst) and an intravenous (Acetadote) formulation, which are similar in efficacy. Because many patients find the taste of the oral solution unpleasant and difficult to tolerate, it should be diluted in a 1:3 ratio with cola, orange juice, or other drink to mask its flavor. This mixture should be used within 1 hour of preparation.

Anaphylactoid reactions have occurred in patients receiving intravenous acetylcysteine for acetaminophen overdose soon after the infusion was started, most commonly during the loading dose. The frequency of infusion-related reactions has been reported to be 0.2% to 20.8%.¹⁵

The recommended dosage for intravenous acetylcysteine is a loading dose of 150 mg/kg given over 60 minutes, followed by a second dose of 50 mg/kg given over 4 hours, and finally a third dose of 100 mg/kg given over 16 hours.¹⁵ For oral acetylcysteine, the loading dose is 140 mg/kg followed by 70 mg/kg every 4 hours for 17 additional doses.¹⁷

Other measures

Activated charcoal can be used if the patient presents within 1 to 2 hours after taking acetaminophen. However, the rapid gastrointestinal absorption of acetaminophen makes this treatment ineffective in most cases.⁹

Liver transplantation. In patients with acute liver failure and a poor prognosis, early referral to a liver transplant center is essential. The King’s College criteria (Table 2),¹⁸ a widely used prognostic model in patients with acute liver failure, are used to predict the need for liver transplantation. They are based on the arterial pH, the PT and INR, the severity of encephalopathy, and the serum creatinine concentration.

FINDINGS FROM LARGE REGISTRIES

Findings in adults

Ostapowicz et al,¹⁹ as part of the Acute Liver Failure Study Group, in 2002 prospectively characterized the short-term outcomes of acute liver failure in a large number of patients at 17 tertiary care centers in the United States over approximately 41 months. All centers except one performed liver transplants. Eligible patients had to meet criteria for acute liver failure, including an INR higher than 1.5, evidence of hepatic encephalopathy, and presentation within 26 weeks of illness onset without apparent chronic liver disease.

Of the 308 cases of acute liver failure, 120 (39%) were from acetaminophen overdose, making this drug the most common cause of acute liver failure. Forty-four (37%) of the patients with acetaminophen-related acute liver failure were trying to commit suicide, 57% of cases were accidental, and the remaining reasons for acetaminophen overdose were unknown. The median amount ingested was 13.2 g/day (range 2.6–75 g), and 99 (83%) of the 120 patients took more than 4 g/day.

The patients with acetaminophen-related acute liver toxicity differed from those with other causes of acute liver failure such as idiosyncratic drug reactions or indeterminate causes. The acetaminophen group had a shorter duration of disease and higher serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine than those with acute liver failure from other causes. They also had lower bilirubin levels and a lower arterial pH.

Rates of liver transplantation were 6% in the acetaminophen group, 53% in the group with other drug-induced liver toxicity, 51% in the indeterminate group, and 36% in the remaining groups. Of the acetaminophen group, 47% met the criteria for transplantation, but only 57% of those eligible were listed for transplantation. Those excluded from the transplant list had medical contraindications or were excluded for psychosocial reasons. The short-term transplant-free survival rate was 68% in the acetaminophen group.

Overall, 11% of the patients died, including 28% of the acetaminophen group. The authors concluded that most cases of liver injury in the United States are due to medications and may be preventable.

Larson et al,²⁰ as part of the Acute Liver Failure Study Group, examined the incidence, risk factors, and outcomes of acetaminopheninduced acute liver failure at 22 tertiary care centers in the United States over a 6-year period. Of the 662 patients in the study, 302 had acetaminophen-related toxicity and 275 were included in the final analysis; some of them had been included in the study by Ostapowicz et al.¹⁹ During the study period, the number of cases of acute liver toxicity related to acetaminophen increased from 28% to 51%.

Of the patients enrolled in the study, 56% met the criteria for potentially toxic acetaminophen ingestion. Of those who met the criteria, 77% had detectable acetaminophen levels in their serum, and 91% had ALT levels higher than 1,000 IU/L. The time between ingestion and symptom onset ranged from 1 to 32 days, and the median dose was 24 g (range 1.2–180 g).

Of the overdose cases, 48% were unintentional, 44% were intentional, and the remaining 8% had no definable reason. Of the patients in the unintentional-overdose group, 38% were using more than one acetaminophen-containing product and 63% were taking combination products containing narcotics. Overeall, 44% of patients reported using narcotic-acetaminophen combination products. The unintentional-overdose group had lower serum acetaminophen levels than the intentional-overdose group, but they were more likely to present with severe hepatic encephalopathy.

The number of patients with an unintentional overdose was worrisome. Furthermore, one-third of the patients who were receiving an acetaminophen-narcotic combination product were taking an additional acetaminophencontaining product. The authors concluded that unintentional overdose is the leading cause of acetaminophen-related hepatotoxicity, and efforts to limit the over-the-counter package size and to restrict prescriptions of acetaminophen-narcotic combinations may be necessary to decrease the incidence of this preventable cause of acute liver failure.

 

 

Findings in children

Squires et al²¹ and the Pediatric Acute Liver Failure Study Group examined the pathogenesis, treatment, and outcome of acute liver failure in children (any age from birth to 18 years) with no previous evidence of chronic liver disease, evidence of acute liver injury, or hepatic-based coagulopathy. From December 1999 to December 2004, 348 patients were enrolled.

Fourteen percent of the cases were due to acetaminophen. The median dose of acetaminophen ingested was 183 mg/kg. Most of these patients were white and female, and 96% were over age 3. Hepatic encephalopathy was more common in the non-acetaminophen groups than in the acetaminophen group, although this is often difficult to assess in infants and children. Children with acetaminophen toxicity had the highest rate of spontaneous recovery: 45 (94%) of 48 recovered.

Although there are fewer acetaminophenrelated cases of acute liver failure in children than in adults, the use of acetaminophen in children is still worrisome. The authors concluded that if they do not have hepatic encephalopathy, children with acetaminopheninduced liver toxicity have an excellent prognosis.

THE FDA LOOKS AT THE PROBLEM

Why overdoses occur

A recent FDA report²² cited the following reasons for acetaminophen overdose:

• Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
• Some patients may be more prone to liver injury from acetaminophen.
• The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
• Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
• Consumers are unaware of the risk of liver toxicity with acetaminophen.
• Prescription products are not always clearly labeled with acetaminophen as an ingredient.
• Pediatric dosage forms are available in many different concentrations.

New package labeling

In view of this information, the FDA has mandated new labeling for acetaminophencontaining products (Table 3).²²

Recommendations from an advisory panel

In addition, an FDA advisory panel recommended decreasing the maximum recommended daily dose (possibly to 3,250 mg/day in adults, although this is not final) to help prevent overdoses, and reducing the maximum amount in a single nonprescription dose of the drug to 650 mg.²³ The panel also voted (by a narrow margin) to ban all acetaminophen-narcotic combination products.

As of this writing, the FDA has not adopted these recommendations. (Although the FDA is not obliged to follow the advice of its advisory panels, in most cases it does.) The recommendations about acetaminophen could take years to implement fully.

THE UNITED KINGDOM ACTED IN 1998

In response to a rising number of analgesicrelated deaths, the United Kingdom enacted legislation in 1998 to limit the package size available to consumers.²⁴ Packages sold in general stores can contain no more than 16 capsules, while those sold in pharmacies can contain 24. Blister packs were also introduced to make it harder for people to impulsively take handfuls of tablets.²⁵

Two studies since then both found that the number of deaths related to paracetamol (as acetaminophen is known in the United Kingdom) had fallen since the legislation was implemented.^24,26 Greene et al²⁷ found that patients who ingested potentially toxic doses of paracetamol had obtained the drug “in a manner contravening the 1998 legislation.”²⁷ In other words, shops in London were not obeying the law.

SUMMARY

The new labeling and the proposed changes are sensible and draw needed attention to the problem of acetaminophen toxicity. To prevent unintentional acetaminophen overdoses, education of patients and health care professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.