Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

BACKGROUND: Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity. METHODS: All patients aged ≥ 16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined. End points included the numbers (%) achieving the target peak concentration [predicted maximum gentamicin concentration (C(max))] >10 mg/L, the target trough concentration at 24 hours [predicted minimum gentamicin concentration (C(min24)] <0.5 mg/L, and the target area under the curve over 24 hours of 70-100 mg/L · h. How these related to various creatinine clearance (CL(cr)) groupings was also examined, as was the number who developed nephrotoxicity (increase in creatinine of ≥ 0.04 mmol/L). RESULTS: After exclusions, information was available on 4523 patients. Of these, 96% achieved the target C(max), 83% the target C(min24), and 54% the target area under the curve over 24 hours. Of the 73% of patients with CL(cr) ≥ 60 mL/min, 98% and 97% achieved the target Cmax and C(min24), respectively. Of the 19% of patients with CL(cr) of 40-59 mL/min, 94% and 61% achieved the target C(max) and C(min24), respectively. Of the 8% of patients with CL(cr) of 20-39 mL/min, 83% and 15% achieved the target Cmax and C(min24), respectively. Nephrotoxicity, "probably" because of gentamicin, was observed in approximately 4% of the patients studied, which was irreversible in 25% of these (ie, 1% overall). CONCLUSIONS: Extending the dose interval of gentamicin to >24 hours is useful in patients with renal impairment to achieve the aims of EID. These results support initial dose intervals for gentamicin of 24, 36, and 48 hours for patients with CL(cr) ≥ 60, 40-59, and 20-39 mL/min, respectively. Irreversible nephrotoxicity was observed in approximately 1% of the patients studied.

The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients.

CONTEXT: Cyclizine, an antihistaminic antiemetic, is commonly used in palliative care. Its pharmacokinetics have been poorly studied, and its metabolic pathway is unknown but may involve the genetically controlled cytochrome P450 2D6 (CYP2D6). If this is the case, the metabolic ratio of cyclizine to norcyclizine and efficacy/adverse effects may vary between patients according to their CYP2D6 genotype. OBJECTIVES: To deduce the pharmacokinetics and antiemetic/sedative effects of cyclizine and relate these and its metabolic ratio to the CYP2D6 genotype in palliative care patients. METHODS: Palliative care patients initiated on continuous cyclizine subcutaneous (SC) infusions had blood samples taken and efficacy/toxicity scores measured during the approach to steady state. Another group of patients at steady state receiving oral cyclizine had a single blood sample taken. Samples were analyzed to elucidate pharmacokinetic parameters and CYP2D6 genetics. RESULTS: SC dosing group: The median (interquartile range) cyclizine half-life, volume of distribution, and clearance were 13 (7-48) hours, 23 (12-30)L/kg, and 15 (11-26)mL/min/kg, respectively. Nausea and sedation scores were 3.0 (1.2-5.7) and 5.0 (2.6-8.1), respectively, overall and did not vary with genotype (P=0.76 and 0.11, respectively). The median overall metabolic ratio at steady state was 4.9 (3.8-9.2) and did vary with CYP2D6 genotype (P=0.02). Oral dosing group: The median metabolic ratio was 2.1 (1.5-2.9) and did not vary with CYP2D6 genotype (P=0.37). CONCLUSION: Palliative care patients have similar cyclizine pharmacokinetics to those reported in other patient groups. Cyclizine metabolism to norcyclizine may include CYP2D6 as the metabolic ratio varied with CYP2D6 genotype in the SC group.

Are gentamicin and/or vancomycin associated with ototoxicity in the neonate? A retrospective audit.

BACKGROUND: Aminoglycoside-induced ototoxicity has been reported in neonates but its incidence is poorly defined, whereas vancomycin-induced ototoxicity has not been reported in neonates. OBJECTIVE: To compare hearing test results in infants in a neonatal intensive care unit (NICU) who were or were not treated with extended interval gentamicin dosing and/or standard vancomycin dosing. METHOD: A database of otoacoustic emissions (OAE), over a 5-year period of NICU admissions, was combined with databases of gentamicin and vancomycin dosing to compare patients treated or not treated with these antibiotics. RESULTS: A total of 2,347 OAE results was available. OAE failure rates were: no gentamicin and no vancomycin (noGnoV), 7% (85/1,233); gentamicin but no vancomycin (GnoV), 4% (42/949); vancomycin but no gentamicin (VnoG), 22% (9/41) and gentamicin and vancomycin (GandV), 14% (17/124). Compared to noGnoV there was a decreased risk of OAE failure in GnoV (p = 0.022, OR 0.64, 95% CI 0.44-0.94) and an increased risk in VnoG (p = 0.003, OR 3.46, 95% CI 1.54-7.75) and GandV, (p = 0.006, OR 2.20, 95% CI 1.26-3.83). CONCLUSIONS: Gentamicin, as used and evaluated in this audit, showed no evidence of an increased risk of ototoxicity; what was observed was a statistically significant decrease in OAE failure rate. Vancomycin, by contrast, was associated with ototoxicity.

Eight years' experience of an extended-interval dosing protocol for gentamicin in neonates.

BACKGROUND: Dosing of gentamicin in neonates in Christchurch has been carried out since 2000 using a locally developed extended-interval dosing protocol. All dosing data have been recorded in a database. AIMS: The aims of this study were to analyse the database to determine what percentage of neonates achieved target values for C(max), C(min) and AUC, and to use the pharmacokinetic values of gentamicin to simulate new dosing protocols. METHODS: C(max), C(min) and AUC were compared with target values. Clearance (CL), volume of distribution (V) and half-life (t(1/2)) were estimated, and used to produce new predictive dosing protocols that were tested and compared with the results of the original protocol. RESULTS: Gentamicin concentrations from 1461 individual doses were recorded in the database. Four hundred and eight were excluded. Of the remaining 1053, 84% achieved the target C(max) (>10 mg/L), 77% the target C(min) (<1 mg/L) and 63% the target AUC (within 80% to 125%). The number achieving target C(max) and C(min) values was improved markedly by prolonging the dosing intervals, but not by altering the predictive equations. Since the majority of the neonates only received a single dose of gentamicin, a new V-based model was also tested, and performed well. CL (L/kg) increased, while V (L/kg) and t(1/2) (h) both decreased with respect to weight. CONCLUSIONS: Extending the dose interval improved the success in achieving target C(max) and C(min), while revision of the dosing equation did not. A V-based model provides an alternative approach to the first dose of gentamicin in neonates.

Protein binding of cefazolin is saturable in vivo both between and within patients.

AIMS: The aims of the study were a) to determine if there is evidence of saturable protein binding of cefazolin in plasma across the range of concentrations achieved clinically (between patient variability) and b) to investigate whether saturable protein binding is also evident from trough and peak concentrations in the same patient (within patient variability). METHODS: Unbound and total plasma concentrations were measured in patients who were treated with cefazolin intravenously by continuous infusion or intermittent injection. In study (i) single random samples were taken from one series of patients. In study (ii) paired samples (troughs and peaks) were taken from a second series of patients. RESULTS: Thirty-one patients were included in study (i). Linear regression analysis of the percentage unbound vs. unbound plasma concentrations revealed a slope significantly different from zero, suggesting saturable protein binding. Mean values for percentage unbound ranged from 9% at low concentrations (8.5 mg l(-1)) to 51% at high concentrations (140 mg l(-1)). Twelve patients were investigated in study (ii). Values for protein binding ranged from 85% at low concentrations (2.7 mg l(-1)) to 52% at high concentrations (200.3 mg l(-1)). The percentage unbound was significantly higher (P < 0.0001) at high (peak) concentrations than at lower (trough) concentrations, confirming saturable protein binding. CONCLUSIONS: The protein binding of cefazolin is saturable in vivo in humans, both between and within patients.

Stability of benzylpenicillin during continuous home intravenous therapy.

OBJECTIVES: The aim of this study was to investigate the temperature profile of home intravenous (iv) antibiotic reservoirs and the stability of 16 megaunits of benzylpenicillin sodium in 120 mL of sodium chloride 0.9% at constant and variable temperatures. METHODS: A Tinytag computerized thermometer recorded temperatures every minute in the home iv antibiotic reservoir pouches of nine patients over a 24 h period. Similar bags containing benzylpenicillin sodium (16 megaunits) were maintained either at a constant 36 degrees C, 26 degrees C or 21-22 degrees C or were worn in a pouch by five healthy volunteers for a 24 h period. Other bags were stored at 3-5 degrees C for 10 days. The bags were sampled at timed intervals and benzylpenicillin concentrations assayed by HPLC. RESULTS: Median temperatures recorded in the infusion bags worn by the nine patients were in the range 16.7-34.1 degrees C. For infusion bags maintained at 36 degrees C, 26 degrees C and 21-22 degrees C, the concentrations of benzylpenicillin dropped below 90% of the initial concentration at a mean time of 5 h 18 min, 12 h 54 min and 13 h 20 min, respectively, whereas for bags worn by the healthy volunteers the mean time for 10% loss of benzylpenicillin was 9 h 20 min. In contrast, at 3-5 degrees C, concentrations of benzylpenicillin only dropped below 90% of the initial concentration at 8 days. CONCLUSIONS: Significant temperature-dependent degradation of benzylpenicillin occurs during continuous home iv antibiotic programme infusions, which could result in loss of efficacy.