Doripenem

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Doribax (Janssen-Cilag)
500 mg powder for reconstitution and infusion
Approved indication: specified infections
Australian Medicines Handbook section 5.1.2

Doripenem is a new carbapenem with broad spectrum activity against Gram-negative or Gram-positive bacteria. However, it does not work against infections caused by methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic is indicated for complicated intra-abdominal infections, nosocomial pneumonia (including ventilator-associated pneumonia) and complicated urinary tract infections (including pyelonephritis and cases of concurrent bacteraemia).

Doripenem is structurally related to the other carbapenems (ertapenem, imipenem, meropenem) which all have a beta lactam ring. The bactericidal activity of these antibiotics comes from their ability to inhibit cell wall synthesis by targeting the bacterial penicillin-binding proteins. In in vitro studies, doripenem has greater activity against Pseudomonas aeruginosa.

Doripenem is given by intravenous infusion every eight hours. For complicated intra-abdominal and urinary tract infections the infusion should be given over one hour, and over one or four hours for pneumonia. Doripenem is not extensively metabolised and most of the dose is excreted unchanged in the urine. Its half-life is approximately one hour in healthy adults.

A lower dose of doripenem is recommended for patients with moderate and severe renal impairment. Doctors should be particularly cautious when using this drug in patients with severely impaired renal function. Although doripenem is haemodialysable, there is insufficient evidence to recommend dose adjustment in those on dialysis. It is probably best avoided in these patients.

The efficacy of doripenem for complicated intra-abdominal infection was similar to that of meropenem in a randomised trial of hospitalised patients. Clinical cure rates (complete resolution or significant improvement of symptoms) were 86% for doripenem and 85% for meropenem in 319 microbiologically evaluable patients (21 to 60 days after completing treatment). More people with P. aeruginosa infections responded to doripenem than meropenem (favourable outcomes in 18/19 patients vs 15/19 patients), however this difference was not significant.¹

Two open-label trials assessed the efficacy of doripenem for nosocomial pneumonia. The first trial compared doripenem to a combination of piperacillin and tazobactam in 444 patients, including some who were ventilated. The median duration of treatment was 11 days. Most patients also received amikacin because of the risk of P. aeruginosa infection. Clinical cure rates were similar for doripenem and piperacillin/tazobactam (81% vs 80%) in the 253 clinically evaluable patients. Not surprisingly, cure rates were lower for patients who were ventilated (69% for doripenem vs 58% for piperacillin/ tazobactam). In the doripenem group, four patients had emergent infections associated with drug-resistant bacteria, including P. aeruginosa, Acinetobacter baumannii and MRSA.²

In the other open-label pneumonia trial, doripenem (given as a 4-hour infusion) was found to be comparable to imipenem in 525 patients who required ventilation. Clinical cure rates were 68% for doripenem and 65% for imipenem in the clinically evaluable population (248 patients). More patients (microbiologically evaluable) with Escherichia coli, Klebsiella pneumoniae and P. aeruginosa infections responded to doripenem than imipenem. Drug resistance emerged inP. aeruginosa isolates during the trial, however this was more common with imipenem than with doripenem.³ (Overall, 38% of patients in the trial were given adjunctive antibiotic treatment for either P. aeruginosa or MRSA.)

The efficacy of doripenem for complicated urinary tract infections and pyelonephritis was found to be comparable to levofloxacin in two trials totalling 1171 patients. One of the trials directly compared doripenem to levofloxacin, and the other trial was an open-label design which used the levofloxacin arm from the other trial for comparative analyses. (As yet, the results of these trials have not been published in full.)

In the pooled microbiologically evaluable populations, cure rates after 10 days of treatment were 82-84% for doripenem and 83% for levofloxacin. Microbiological cure rates were lower for renally impaired patients who received a lower dose of the intravenous study drug (75% (54/72 patients) for doripenem and 58% (15/26 patients) for levofloxacin). More infections emerged during doripenem treatment than levofloxacin treatment. Isolates included Enterococcus faecali, E. coli, Enterobacter cloacae, K. pneumoniae, P. aeruginosa and Serratia marcescens. Similarly, super infections (those caused by resistant pathogens) were more common with doripenem. Resistant organisms included Candida species, Enterococcus species, E. coli, Myroides species, S. aureus and S. maltophilia.

The most common adverse events with doripenem in the clinical trials were headache (10%), diarrhoea (9%) and nausea (8%). Occasionally more serious adverse events have occurred that were thought to be related to doripenem. These included atrial fibrillation, atrial flutter, acute renal failure, renal impairment, cholestasis, abnormal liver function test, convulsion and hypotension. Treatment was discontinued in 1 in every 1000 patients - reasons included nausea, diarrhoea, pruritus, vulvomycotic infection, increased hepatic enzymes and rash.

As with other carbapenems, doripenem may reduce sodium valproate concentrations in serum, so concentrations should be monitored. An alternative antibiotic or anticonvulsant may be needed if therapeutic doses of valproate cannot be maintained or if seizures occur. Probenecid reduces the renal clearance of doripenem therefore co-administration of these drugs is not recommended. Doripenem is contraindicated in patients who are allergic to penicillins and other beta lactam antibiotics.

Doripenem offers an alternative for patients with serious infections when other treatments have failed, however the approval of this drug is mainly based on data from non-inferiority trials.⁴ As with the other carbapenems, bacterial resistance is a problem. Although in vitro studies show that doripenem has increased activity against P. aeruginosa, there are limited data from the trials to suggest this is also the case in infected patients.

manufacturer provided only the product information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes of references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).