Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients with Sepsis.

BACKGROUND: Doripenem is approved by the Food and Drug Administration for the treatment of patients with complicated intra-abdominal infections and complicated urinary tract infections. While studies have described the pharmacokinetics/pharmacodynamics (PK/PD) of doripenem in the critically ill, no study has described the probability of target attainment profile among trauma patients with sepsis. PATIENTS AND METHODS: This study was a prospective, open-label, pharmacokinetic study in the surgical intensive care unit (SICU) at Grady Health System. Thirty trauma patients with sepsis admitted to the SICU received doripenem 1 g infused over 4 hours every 8 hours for three doses. Blood samples were taken just before and after the third dose. A two-compartment model was fit to the data using non-parametric population PK modeling software. Embedded with the final PK model, a Monte Carlo Simulations (MCS) was performed to determine the PK/PD profile of doripenem 1 g, infused over 4 hours, every 8 hours after administration of the first and fourth doses. RESULTS: Overall, the model fit the data well, and mean (standard deviation) clearance and volume of the central compartment were 16.9 (11.4) L/h and 28.5 (16.0) L, respectively. In the MCS analyses, doripenem 1 g, infused over 4 hours, administered every 8 hours, conferred >90% probabilities of achieving 30-50% time greater than the minimum inhibitory concentration (30-50% T>MIC) for MICs ≤2 mg/L after infusion of both the first and fourth doses. The MCS indicated that more intensive doripenem dosing schemes should be considered for organisms with MIC values in excess of 2 mg/L. CONCLUSIONS: This is the first study to describe the doripenem PK/PD in critically ill patients with trauma. Among these patients, the MCS analyses suggest that current dosing strategies may be ineffective when the MIC value for the infecting pathogen is expected to be above 2 mg/L.

Azithromycin-induced liver injury.

PURPOSE: A case of azithromycin-induced hepatotoxicity in a 69-year-old woman with no history of liver disease is reported. SUMMARY: After receiving four days of high-dose azithromycin for the treatment of suspected bronchitis, a 69-year-old woman arrived at the emergency room with nausea, vomiting, diarrhea, elevated liver enzyme values, and visible signs of pruritus and jaundice. Her medical history included hypertension, hypothyroidism secondary to Graves disease, depression, dyslipidemia, and chronic obstructive pulmonary disease. She had no history of liver, cardiac, genitourinary, and renal diseases. Causes of primary liver injury, including metabolic, viral, and autoimmune liver diseases, were excluded. Her International Normalized Ratio was elevated, and substantial transaminitis was noted. There was no evidence of portal vein thrombosis on ultrasound, and extrahepatic obstruction was unlikely. Liver injury associated with right heart failure was unlikely, as right ventricular function was relatively preserved and right atrial pressure was not severely elevated. Ischemic hepatitis was also ruled out. After exclusion of other causes of liver disease, drug-induced hepatotoxicity was considered. A careful review of her medications prior to admission was conducted. A temporal relationship between initiation of azithromycin and the onset of clinical signs and symptoms was noted. The Naranjo et al. probability scale indicated a possible relationship between azithromycin and hepatotoxicity; however, two scales specifically used for evaluating drug-induced liver disease indicated a probable adverse drug-associated event. CONCLUSION: A 69-year-old woman developed cholestatic hepatitis after four days of therapy with high-dose azithromycin for the treatment of suspected bronchitis.