Doripenem appeared to be non-inferior in Phase III trials to meropenem for the treatment of intra-abdominal infections, levofloxacin for urinary tract infections, and imipenem and piperacillin/tazobactam for nosocomial pneumonia. However, the reliability of the review methods and data were unclear, so the authors' findings may not be valid and should be interpreted with caution.

To review doripenem, a broad-spectrum antibiotic, for the management of complicated bacterial infections. The evidence reviewed relates to the drug's chemistry, spectrum of activity, mechanisms of resistance, pharmacokinetics, interactions with other drugs, effectiveness, tolerability, dosing and administration. Only data relating to effectiveness and tolerability are reported in this review abstract.

MEDLINE (from 1996) and BIOSIS Previews (from 1993) were searched for English-language articles up to October 2008. Search terms were reported. Reference lists of retrieved publications and abstracts from the Conference on Antimicrobial Agents and Chemotherapy (2003-2007) were screened for additional studies. Drug manufacturers were contacted for further information.

The authors did not report inclusion/exclusion criteria. However, it was evident from the review title and aims that studies that assessed the effectiveness and tolerability of doripenem for the treatment of individuals with complicated bacterial infections were eligible for inclusion in the review.

Phase II studies of between 250 and 1,000 milligrams per day (mg/d) of doripenem administered in two or three divided doses and phase III trials of 500mg/d of doripenem administered every eight hours, usually as a 60-minute infusion, were included in the review. The duration of administration varied, but was usually over a period of between five or seven hours to 14 hours. Control groups were treated with intravenous imipenem (500mg every six hours), piperacillin/tazobactam (4.5g every eight hours), meropenem (1g every eight hours) or levofloxacin (250g every 24 hours). Included participants were adults with nosocomial pneumonia, intra-abdominal infections or urinary tract infections; where stated, most included participants in each study were white males.

The authors stated neither how papers were selected for review nor how many reviewers performed the selection.

The authors did not state that they assessed validity.

The authors stated neither how data were extracted for the review nor how many reviewers performed the data extraction. For included phase III studies, the number of patients included and the percentage clinical cure rate were reported for the clinical modified intention to treat (cMITT) population and those who were clinically evaluable, and the microbiologic modified intention to treat (mMITT) population and those who were microbiologically evaluable.

Studies were grouped by study phase and type of bacterial infection, and described in a narrative summary accompanied by data tables. Some differences between the studies were evident from the text and tables.

Five Phase III RCTs (n=2,414) were included in the review. Sample sizes ranged from 448 to 531.

Doripenem appeared to be non-inferior to: meropenem for the treatment of intra-abdominal infections (difference in clinical cure rate was -2.1%; 95% CI: -9.8 to 5.6; one study); levofloxacin for urinary tract infections (difference in clinical cure rate was 4.9%; 95% CI: 0.2 to 9.6; one study); and imipenem (difference in clinical cure rate was 3.5%; 95% CI: -9.1 to 16.1; one study) and piperacillin/tazobactam (difference in clinical cure rate was 1.5%; 95% CI: -9.1 to 12.1; one study) for nosocomial pneumonia.

Percentage clinical cure rates were also reported for cMITT populations, microbiologically evaluable populations and mMITT populations in each study.

The incidence of adverse events was comparable between doripenem and all of its comparators. The main adverse effects experienced by patients treated with doripenem were: anaphylaxis and rash; gastrointestinal effects (including nausea, diarrhea and vomiting); and central nervous system effects (including headache, insomnia, anxiety and rarely seizures).

Data in abstract form from two Phase II studies were also reported in the review.

Doripenem appeared to be non-inferior in Phase III trials to meropenem for the treatment of intra-abdominal infections as well as levofloxacin for urinary tract infections and imipenem and piperacillin/tazobactam for nosocomial pneumonia.

This review did not define specific inclusion criteria for study design, population, intervention or outcome beyond those implied by the review title and aim. Searches were carried out to look for both published and unpublished data, however, relevant studies may have been missed through the inclusion of only English language studies and the review is at risk from language bias. The searches were also limited by date without justification, but this was likely to be due to the introduction of the drug into clinical practice. The reliability of the review methods was unclear, as the methods of the review were not reported. There also appeared to be no assessment of study validity, so it was difficult to assess the reliability of the data. The authors reported carrying out a subgroup analysis according to study quality. Given the differences in comparators and populations between the included studies, a narrative summary of the review findings appeared appropriate. Some study details and data were summarised in a table. A further table summarising the population characteristics would have been helpful. Outcomes were reported according to intention to treat and per protocol analysis of those patients who were clinically and microbiologically evaluable, thereby providing both conservative and more optimistic summaries of the relative effectiveness of doripenem and its comparators. In addition, all of the studies were carried out recently and so were likely to reflect the susceptibility of currently circulating bacterial strains. In each case the review findings were based on single studies for each comparison, so the reliability of the findings was unclear. Overall, the reliability of the review methods and the data was unclear, so the authors' findings may not be valid and should be interpreted with caution.

Practice: The authors stated that further cost-effectiveness studies of doripenem in comparison with other agents with similar antimicrobial activity were required.

Research: The authors stated that given the risk of selecting for drug resistant organisms, doripenem should be reserved only for the treatment of serious infections where multidrug-resistant gram-negative bacteria, polymicrobial infections or infections by Pseudomonas aeruginosa were suspected.

Not reported.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.