Kate Johnson

September 07, 2014

WASHINGTON — Quadrupling the US Food and Drug Administration's approved dose of the powerful antibiotic doripenem (Doribax, Shionogi & Co, Ltd) in patients with cystic fibrosis (CF) and acute respiratory infection is safe and could offer a new therapeutic option for those with advanced disease and evidence of resistant bacteria in their lungs, a new study suggests.

"There is concern about what high doses of antibiotics will do to these patients from a side-effect profile, but our study suggests the safety of high-dose doripenem in this population," said lead investigator Michael Nailor, PharmD, from the University of Connecticut School of Pharmacy, in Storrs, and Hartford Hospital.

"It is manageable and does not lead to discontinuation due to side effects," he told Medscape Medical News.

The study results were presented here at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

The retrospective, single-site chart review included 16 CF patients (median age, 24 years) with hospital admissions during a 3-year period who were given high-dose doripenem. Two-gram doses were administered intravenously every 8 hours — for acute respiratory infection for a mean of 8.9 days.

The rate of adverse events was high (a mean of 2 events per patient) but not uncommon for this population. Concomitant antibiotic use was also high (a mean of 3.2 per admission), and the researchers suggest that this could have contributed to anemia and gastrointestinal complaints, including diarrhea (25.6%), nausea, vomiting or antiemetic use (20.9%), Clostridium difficile infection (7%), and oral candidiasis/oral nystatin use (7%).

Other adverse events included headache (14%) and pruritus, antihistamine use, or rash (4.7%).

In addition, doripenem was temporarily discontinued in 1 patient because of concern of an anaphylactic reaction; however, the patient was rechallenged with no adverse effect. Another patient developed leukopenia, but doripenem was not discontinued, nor was the dose reduced, and laboratory results returned to normal after 1 day, Dr. Nailor reported.

High Dose

As a result of the findings, "we use this high dose of doripenem in CF patients who have previously had resistant bacteria isolated up front when they come to the hospital, since there is a high rate of resistance in these patients," said Dr. Nailor.

In particular, he added, colonization with Pseudomonas aeruginosa is an indication for this approach, because "this organism is almost impossible to eradicate in CF patients."

"Initially, it can be treated with many antibiotics, but after repeated therapies, it can become resistant to many or sometimes all of them, but just barely resistant to doripenem," he explained. "In these cases, previously published models suggest that the dose we used in our study should overcome that."

Asked to comment on the results, Andrea Kemper, PharmD, who was not involved with the study, said she agrees that high-dose doripenem should be considered in the CF population.

Dr. Kemper and her group from the Intermountain Primary Children's Medical Center and Intermountain Cystic Fibrosis Pediatric Center, in Salt Lake City, Utah, have previously studied high-dose doripenem in a children with CF ( Pediatr Pulmonol. 2014 Mar;49:E48-51).

"Since we studied a pediatric CF population, the doses our patients received were not quite as high as the 2 grams IV every 8 hours that were utilized in this new study," she told Medscape Medical News. "However, I agree with the investigators regarding the safety implications, as we also found similar adverse events, which were relatively minor and transient."

She added that an intermittent extended infusion regimen during a 4-hour period is also worth considering, particularly when high minimum inhibitory concentrations (MIC) of organisms are identified.

"Since it appears that doripenem has a shorter elimination half-life in CF patients, the time in which the drug concentration exceeds the MIC (T > MIC) may not be adequate," said Dr. Kemper. "Previous studies have shown the inability for higher intermittent dosing regimens of beta lactams to achieve adequate time above the MIC, possibly rendering these regimens ineffective and necessitating extended infusion or continuous infusion regimens."

Dr. Nailor said he agrees. "Although it was not a specific inclusion/exclusion criteria in the study, virtually all of our patients did receive the doripenem over 4 hours." However, because of logistical problems, "not every dose is given in such a way."

Dr. Nailor and Dr. Kemper report no relevant financial relationships.

54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract K-368. Presented September 6, 2014.

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