Pharmacodynamics of Ceftizoxime
Study Objective. Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class-specific pharmacodynamics. Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cpmin) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function.
Design. Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages.
Setting. University-affiliated hospital.
Patients. Forty-three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Clcr; ml/min): group 1, above 100; group 2, 61-99; group 3, 31-60; and group 4, 15-30.
Interventions. Ceftizoxime serum concentrations were obtained at steady state.
Measurements and Main Results. Pharmacokinetic and pharmacodynamic parameters were calculated. As expected, clearance and elimination rate constant were reduced, and half-life tended to be greater in patients with renal impairment. The Cpmin and area under the concentration-time curve over 24 hours were similar between groups (p=0.39, p=0.42). The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups. Clinical outcomes were similar among all groups.
Conclusion. Our dosing guidelines achieved similar Cpmin among all groups of patients. Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.
Estimated renal function is used to determine dosing of aminoglycosides and vancomycin, but it is often overlooked with other antimicrobials such as ß-lactams. The elimination of many penicillins and cephalosporins is significantly dependent on glomerular filtration. If the dosage of these antimicrobials is not adjusted according to the degree of renal impairment, drug accumulation may occur secondary to reduced clearance, and excessive serum concentrations may result. Consequently, this may be associated with a higher likelihood of adverse drug events as well as an unnecessary increase in drug acquisition and administration costs.
It is necessary to reduce dosages of renally eliminated antibiotics based on renal function to prevent toxicity related to drug accumulation. Although ß-lactams have a relatively good safety profile, high dosages of intravenous penicillin have been associated with symptoms such as hallucinations, hyperreflexia, myoclonus, and generalized seizures. Cephalosporins have caused central nervous system toxicity such as hallucinations and seizures in patients with renal insufficiency. One group concluded that even though penicillins and first-generation cephalosporins are more widely reported to cause neurotoxicity, excessively high dosages of a third-generation cephalosporin may also result in such symptoms. These authors described neurotoxic symptoms such as confusion, restlessness, and myoclonus in two elderly patients with renal impairment who received excessive ceftazidime dosages based on their age and renal function. Since factors such as excessively high dosages, renal dysfunction, and old age may be associated with increased risk of toxicity, dosage adjustments based on renal function are necessary to minimize the risk of adverse drug events. In addition to providing a safe regimen, it is important that these adjustments produce therapeutic concentrations similar to those provided with standard regimens in patients with normal renal function.
Renally adjusted dosages should take into account class-specific pharmacodynamics to ensure optimal bacterial killing. Since most ß-lactams have concentration-independent killing, the rate and extent of bacterial kill remain constant once a concentration above the minimum inhibitory concentration (MIC) is achieved. Since achieving high peak concentration does not contribute to killing activity, the best approach appears to decrease the dose and maintain the same interval. If further reduction is necessary, the interval should be extended. Although the optimal percentage of time above the MIC of the infecting organism (T>MIC) varies, it was proposed that achieving T>MIC between 40% and 100% of the dosing interval is associated with optimal outcome. Consequently, renally adjusted dosages should achieve similar T>MIC profiles as standard regimens in patients with normal renal function in order to achieve similar outcomes.
Medical references provide dosage recommendations based on a patient's degree of renal dysfunction. The recommendations are inconsistent, however, and based on data obtained primarily from healthy volunteers (Table 1). There is little documentation that these adjusted regimens achieve therapeutic levels in infected patients. By calculating the total clearance of ceftizoxime and predicting the minimum plasma concentration (Cpmin) attained using these recommendations, a wide range of Cpmin and T>MIC exists (Table 2). These recommendations provide safe dosages but may not necessarily achieve optimum pharmacodynamics of ß-lactams.
We attempted to validate that the ceftizoxime renally adjusted dosage guidelines used at our institution achieve Cpmin comparable with those produced in patients without renal dysfunction. Pharmacokinetic and pharmacodynamic parameters of ceftizoxime in patients with various degrees of renal function were secondary end points.
Study Objective. Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class-specific pharmacodynamics. Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cpmin) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function.
Design. Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages.
Setting. University-affiliated hospital.
Patients. Forty-three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Clcr; ml/min): group 1, above 100; group 2, 61-99; group 3, 31-60; and group 4, 15-30.
Interventions. Ceftizoxime serum concentrations were obtained at steady state.
Measurements and Main Results. Pharmacokinetic and pharmacodynamic parameters were calculated. As expected, clearance and elimination rate constant were reduced, and half-life tended to be greater in patients with renal impairment. The Cpmin and area under the concentration-time curve over 24 hours were similar between groups (p=0.39, p=0.42). The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups. Clinical outcomes were similar among all groups.
Conclusion. Our dosing guidelines achieved similar Cpmin among all groups of patients. Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.
Estimated renal function is used to determine dosing of aminoglycosides and vancomycin, but it is often overlooked with other antimicrobials such as ß-lactams. The elimination of many penicillins and cephalosporins is significantly dependent on glomerular filtration. If the dosage of these antimicrobials is not adjusted according to the degree of renal impairment, drug accumulation may occur secondary to reduced clearance, and excessive serum concentrations may result. Consequently, this may be associated with a higher likelihood of adverse drug events as well as an unnecessary increase in drug acquisition and administration costs.
It is necessary to reduce dosages of renally eliminated antibiotics based on renal function to prevent toxicity related to drug accumulation. Although ß-lactams have a relatively good safety profile, high dosages of intravenous penicillin have been associated with symptoms such as hallucinations, hyperreflexia, myoclonus, and generalized seizures. Cephalosporins have caused central nervous system toxicity such as hallucinations and seizures in patients with renal insufficiency. One group concluded that even though penicillins and first-generation cephalosporins are more widely reported to cause neurotoxicity, excessively high dosages of a third-generation cephalosporin may also result in such symptoms. These authors described neurotoxic symptoms such as confusion, restlessness, and myoclonus in two elderly patients with renal impairment who received excessive ceftazidime dosages based on their age and renal function. Since factors such as excessively high dosages, renal dysfunction, and old age may be associated with increased risk of toxicity, dosage adjustments based on renal function are necessary to minimize the risk of adverse drug events. In addition to providing a safe regimen, it is important that these adjustments produce therapeutic concentrations similar to those provided with standard regimens in patients with normal renal function.
Renally adjusted dosages should take into account class-specific pharmacodynamics to ensure optimal bacterial killing. Since most ß-lactams have concentration-independent killing, the rate and extent of bacterial kill remain constant once a concentration above the minimum inhibitory concentration (MIC) is achieved. Since achieving high peak concentration does not contribute to killing activity, the best approach appears to decrease the dose and maintain the same interval. If further reduction is necessary, the interval should be extended. Although the optimal percentage of time above the MIC of the infecting organism (T>MIC) varies, it was proposed that achieving T>MIC between 40% and 100% of the dosing interval is associated with optimal outcome. Consequently, renally adjusted dosages should achieve similar T>MIC profiles as standard regimens in patients with normal renal function in order to achieve similar outcomes.
Medical references provide dosage recommendations based on a patient's degree of renal dysfunction. The recommendations are inconsistent, however, and based on data obtained primarily from healthy volunteers (Table 1). There is little documentation that these adjusted regimens achieve therapeutic levels in infected patients. By calculating the total clearance of ceftizoxime and predicting the minimum plasma concentration (Cpmin) attained using these recommendations, a wide range of Cpmin and T>MIC exists (Table 2). These recommendations provide safe dosages but may not necessarily achieve optimum pharmacodynamics of ß-lactams.
We attempted to validate that the ceftizoxime renally adjusted dosage guidelines used at our institution achieve Cpmin comparable with those produced in patients without renal dysfunction. Pharmacokinetic and pharmacodynamic parameters of ceftizoxime in patients with various degrees of renal function were secondary end points.