Shorter Treatment Failed for Ventilator-Assisted Pneumonia

SAN FRANCISCO – A phase III clinical trial ended early after preliminary results showed lower cure rates and higher death rates in patients with ventilator-associated pneumonia who were treated for 7 days with doripenem, compared with patients who received 10 days of imipenem.

With 274 patients randomized of a planned enrollment of 524 participants, the investigators conducted a modified intention-to-treat analysis of patients with qualifying bacterial organisms confirmed by bronchiolar lavage and culture. Clinical cure rates were 46% for doripenem and 57% for imipenem, and 28-day all-cause mortality rates were 22% for doripenem and 15% for imipenem, Dr. Marin H. Kollef and his associates reported in a late-breaker session at an international the conference of the American Thoracic Society.

The confidence intervals for both results crossed the threshold of no greater than a 15% difference between groups that would be required to say the doripenem regimen was noninferior to the imipenem regimen. Multiple overall and subgroup analyses showed trends favoring the safety and efficacy of the imipenem regimen, said Dr. Kollef, professor of medicine at Washington University and director of the medical ICU and of respiratory care services at Barnes-Jewish Hospital, both in St. Louis.

The difference in 28-day all-cause mortality did reach statistical significance in a subgroup of patients infected with P. aeruginosa, who were more likely to survive on imipenem therapy, he said.

Doripenem is a carbapenem antibiotic that is approved in the United States for the treatment of complicated urinary and abdominal infections caused by susceptible bacteria but is not approved for pneumonia. It is approved in many other countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

The study, known as the DORINOS3008 study, used a higher dose of doripenem than is approved in other countries for pneumonia, the thinking being that a higher dosage might allow shorter duration of treatment. Patients randomized to doripenem received 1 g of doripenem in a 4-hour infusion every 8 hours for 7 days plus a 1-hour infusion of saline placebo every 8 hours for 10 days. The imipenem group received a 4-hour infusion of placebo every 8 hours for 7 days and a 1-hour infusion of imipenem every 8 hours for 10 days.

In the doripenem group, 44% of patients reached a creatinine clearance of at least 150 mL/min, compared with 71% of patients in the imipenem group.

The findings contradict results of a previous phase III study of VAP treated for 7-10 days at the discretion of the investigator. That study, known as DORI-10, reported noninferiority between a regimen of doripenem 500 mg in 4-hour infusions every 8 hours and treatment with imipenem 500 mg in 30-minute infusions every 6 hours or 1 g in 60-minute infusions every 8 hours. In that study, more than 90% of cured patients were treated for at least 8 days, and 35% of patients were treated for at least 10 days, Dr. Kollef noted (Crit. Care Med. 2008;36:1089-96).

In countries where doripenem is approved to treat ventilator-associated pneumonia, the usual duration of treatment is 7-14 days.

"I can’t give you the absolute explanation" for the differences in results from DORI-10 and DORINOS3008, but the findings suggest that physicians should consider treating VAP for longer than 7 days, Dr. Kollef said.

The current study included adult patients who had been hospitalized for at least 5 days, who were on mechanical ventilation, and who met clinical and radiographic criteria for pneumonia.

The study was funded by Johnson & Johnson, which markets doripenem. Dr. Kollef has been a speaker for Pfizer.

SAN FRANCISCO – A phase III clinical trial ended early after preliminary results showed lower cure rates and higher death rates in patients with ventilator-associated pneumonia who were treated for 7 days with doripenem, compared with patients who received 10 days of imipenem.

With 274 patients randomized of a planned enrollment of 524 participants, the investigators conducted a modified intention-to-treat analysis of patients with qualifying bacterial organisms confirmed by bronchiolar lavage and culture. Clinical cure rates were 46% for doripenem and 57% for imipenem, and 28-day all-cause mortality rates were 22% for doripenem and 15% for imipenem, Dr. Marin H. Kollef and his associates reported in a late-breaker session at an international the conference of the American Thoracic Society.

The confidence intervals for both results crossed the threshold of no greater than a 15% difference between groups that would be required to say the doripenem regimen was noninferior to the imipenem regimen. Multiple overall and subgroup analyses showed trends favoring the safety and efficacy of the imipenem regimen, said Dr. Kollef, professor of medicine at Washington University and director of the medical ICU and of respiratory care services at Barnes-Jewish Hospital, both in St. Louis.

The difference in 28-day all-cause mortality did reach statistical significance in a subgroup of patients infected with P. aeruginosa, who were more likely to survive on imipenem therapy, he said.

Doripenem is a carbapenem antibiotic that is approved in the United States for the treatment of complicated urinary and abdominal infections caused by susceptible bacteria but is not approved for pneumonia. It is approved in many other countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

The study, known as the DORINOS3008 study, used a higher dose of doripenem than is approved in other countries for pneumonia, the thinking being that a higher dosage might allow shorter duration of treatment. Patients randomized to doripenem received 1 g of doripenem in a 4-hour infusion every 8 hours for 7 days plus a 1-hour infusion of saline placebo every 8 hours for 10 days. The imipenem group received a 4-hour infusion of placebo every 8 hours for 7 days and a 1-hour infusion of imipenem every 8 hours for 10 days.

In the doripenem group, 44% of patients reached a creatinine clearance of at least 150 mL/min, compared with 71% of patients in the imipenem group.

The findings contradict results of a previous phase III study of VAP treated for 7-10 days at the discretion of the investigator. That study, known as DORI-10, reported noninferiority between a regimen of doripenem 500 mg in 4-hour infusions every 8 hours and treatment with imipenem 500 mg in 30-minute infusions every 6 hours or 1 g in 60-minute infusions every 8 hours. In that study, more than 90% of cured patients were treated for at least 8 days, and 35% of patients were treated for at least 10 days, Dr. Kollef noted (Crit. Care Med. 2008;36:1089-96).

In countries where doripenem is approved to treat ventilator-associated pneumonia, the usual duration of treatment is 7-14 days.

"I can’t give you the absolute explanation" for the differences in results from DORI-10 and DORINOS3008, but the findings suggest that physicians should consider treating VAP for longer than 7 days, Dr. Kollef said.

The current study included adult patients who had been hospitalized for at least 5 days, who were on mechanical ventilation, and who met clinical and radiographic criteria for pneumonia.

The study was funded by Johnson & Johnson, which markets doripenem. Dr. Kollef has been a speaker for Pfizer.

SAN FRANCISCO – A phase III clinical trial ended early after preliminary results showed lower cure rates and higher death rates in patients with ventilator-associated pneumonia who were treated for 7 days with doripenem, compared with patients who received 10 days of imipenem.

With 274 patients randomized of a planned enrollment of 524 participants, the investigators conducted a modified intention-to-treat analysis of patients with qualifying bacterial organisms confirmed by bronchiolar lavage and culture. Clinical cure rates were 46% for doripenem and 57% for imipenem, and 28-day all-cause mortality rates were 22% for doripenem and 15% for imipenem, Dr. Marin H. Kollef and his associates reported in a late-breaker session at an international the conference of the American Thoracic Society.

The confidence intervals for both results crossed the threshold of no greater than a 15% difference between groups that would be required to say the doripenem regimen was noninferior to the imipenem regimen. Multiple overall and subgroup analyses showed trends favoring the safety and efficacy of the imipenem regimen, said Dr. Kollef, professor of medicine at Washington University and director of the medical ICU and of respiratory care services at Barnes-Jewish Hospital, both in St. Louis.

The difference in 28-day all-cause mortality did reach statistical significance in a subgroup of patients infected with P. aeruginosa, who were more likely to survive on imipenem therapy, he said.

Doripenem is a carbapenem antibiotic that is approved in the United States for the treatment of complicated urinary and abdominal infections caused by susceptible bacteria but is not approved for pneumonia. It is approved in many other countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

The study, known as the DORINOS3008 study, used a higher dose of doripenem than is approved in other countries for pneumonia, the thinking being that a higher dosage might allow shorter duration of treatment. Patients randomized to doripenem received 1 g of doripenem in a 4-hour infusion every 8 hours for 7 days plus a 1-hour infusion of saline placebo every 8 hours for 10 days. The imipenem group received a 4-hour infusion of placebo every 8 hours for 7 days and a 1-hour infusion of imipenem every 8 hours for 10 days.

In the doripenem group, 44% of patients reached a creatinine clearance of at least 150 mL/min, compared with 71% of patients in the imipenem group.

The findings contradict results of a previous phase III study of VAP treated for 7-10 days at the discretion of the investigator. That study, known as DORI-10, reported noninferiority between a regimen of doripenem 500 mg in 4-hour infusions every 8 hours and treatment with imipenem 500 mg in 30-minute infusions every 6 hours or 1 g in 60-minute infusions every 8 hours. In that study, more than 90% of cured patients were treated for at least 8 days, and 35% of patients were treated for at least 10 days, Dr. Kollef noted (Crit. Care Med. 2008;36:1089-96).

In countries where doripenem is approved to treat ventilator-associated pneumonia, the usual duration of treatment is 7-14 days.

"I can’t give you the absolute explanation" for the differences in results from DORI-10 and DORINOS3008, but the findings suggest that physicians should consider treating VAP for longer than 7 days, Dr. Kollef said.

The current study included adult patients who had been hospitalized for at least 5 days, who were on mechanical ventilation, and who met clinical and radiographic criteria for pneumonia.

The study was funded by Johnson & Johnson, which markets doripenem. Dr. Kollef has been a speaker for Pfizer.