Doripenem: A new extended-spectrum carbapenem antibiotic

Key Points

Abstract

Doripenem is a carbapenem antibiotic recently approved for the treatment of complicated intra-abdominal infections (IAIs) and complicated urinary tract infections (UTIs), including pyelonephritis. An NDA has also been submitted for the use of doripenem in the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP). Doripenem is the fourth carbapenem approved for use in the United States and exhibits many pharmacologic similarities with imipenem/cilastatin and meropenem. Doripenem has a broad spectrum of activity against various gram-positive and gram-negative aerobic and anaerobic bacteria, including many multidrug-resistant gram-negative pathogens. Improved potency against nonfermentative gram-negative bacteria has also been demonstrated with doripenem compared with other carbapenems. In clinical trials, doripenem was generally well tolerated; headache, nausea, diarrhea, and phlebitis were the most commonly reported drug-related adverse events. Because doripenem exhibits similarities with imipenem/cilastatin and meropenem, it is likely that institutional susceptibility patterns and cost may be the 2 factors that will carry the most weight in formulary decisions. (Formulary. 2007;42:676–688.)

Infections secondary to drug-resistant pathogens continue to present therapeutic challenges to clinicians. Because a number of the historically most active antimicrobials have undergone widespread susceptibility diminution, healthcare professionals are now presented with scenarios in which infecting microbes are resistant to all but a handful of antibiotics. Pathogens that have emerged as particularly problematic include gram-positive microbes such as Staphylococcus aureus and Enterococcus species; extended-spectrum, AmpC, and metallobeta-lactamase-producing Enterobacteriaceae; and nonfermentative gram-negative species such as Acinetobacter species and Pseudomonas aeruginosa.^1,2

Four carbapenems are currently approved for use in the United States (dori-penem, meropenem, imipenem/cilastatin, and ertapenem). Ertapenem is considered a narrower spectrum agent, as it has limited activity against certain pathogens of concern such as P aeruginosa. The other 3 carbapenems have a broader spectrum of activity and are considered a distinct subclass of the carbapenems.

Despite the carbapenems' broad spectrum of activity and the positive clinical outcomes associated with these agents, problems of drug stability, shortages, side effects such as reduced seizure threshold, and the emergence of isolates that demonstrate carbapenem resistance threaten to limit the use of these drugs. As a result, the introduction of a new agent into this class of antibiotics represents a potentially significant addition to the antimicrobial armamentarium.

Doripenem (Doribax, Johnson & Johnson) was approved on October 12, 2007, as a single agent for the treatment of complicated IAIs and for the treatment of complicated UTIs, including pyelonephritis. An NDA has also been submitted for the use of doripenem in the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).⁵

CHEMISTRY AND PHARMACOLOGY

Doripenem is a carbapenem antibiotic with a broad spectrum of activity.⁶ As with other drugs in its class, doripenem has a carbon atom in position 1 of its structure and a trans configuration of the hydroxyethyl group.^7,8 These features differentiate the carbapenems from other beta-lactam antibiotics and promote stability against the majority of beta-lactamases (including extended-spectrum beta-lactamases).^8,9

Doripenem also contains a 1-beta methyl side chain (similarly present in meropenem and ertapenem).^10,11 This side chain prevents hydrolysis by renal dehydropeptidase-1 and allows for administration without concurrent use of a dehydropeptidase-1 inhibitor. Imi-penem does not contain a 1-beta methyl side chain and consequently is administered with a dehydropeptidase-1 inhibitor (cilastatin) to decrease the metabolism of imipenem and to sustain antimicrobial efficacy.

Doripenem's side chain contains a sulfamoylaminomethyl-pyrrolidinylthio group, which may contribute to enhanced gram-negative antimicrobial activity.^10,11 As with other beta-lactam antimicrobials, doripenem exerts its antibacterial effect by binding to penicillin-binding proteins (PBPs), leading to inhibition of cell wall synthesis.^6,7

PHARMACOKINETICS AND PHARMACODYNAMICS

Doripenem's pharmacokinetic profile has been evaluated after intravenous (IV) administration of doses ranging from 125 to 1,000 mg.^12–16 The pharmacokinetic profile of doripenem is similar to the profiles of meropenem and imipenem/ cilastatin; each have a half-life of approximately 1 hour in patients with normal renal function. Protein binding of doripenem is approximately 8% compared with meropenem (2%) and imipenem (20%).^6,17,18 In contrast, ertapenem is highly protein bound (approximately 85%–95%) and subsequently has an extended half-life (approximately 4 h in adults with normal renal function).¹⁹ All 4 approved carbapenems are predominately excreted unchanged in the urine and require dose adjustment in patients with renal dysfunction.^6,17–19

Approximately 70% to 75% of a doripenem dose is excreted in the urine as unchanged drug.^12–14 Clearance is reduced in patients with renal impairment, resulting in an increased half-life (Table 1).¹² In a phase 1 study that evaluated 24 patients with varying degrees of renal impairment, the average half-life of dori-penem increased from approximately 1 hour in healthy matched control volunteers (n=8) to almost 9 hours in patients with end-stage renal disease who were not yet undergoing dialysis.¹² As a result, dose adjustment is warranted for patients with impaired renal function (creatinine clearance [CrCl] ≤50 mL/min). Data regarding the pharmacokinetics of doripenem in patients with hepatic impairment are currently lacking.

Doripenem, similar to other carba-penems, exhibits non-concentration-dependent activity. Optimal activity may be expected if drug concentrations can be maintained above the minimum inhibitory concentration (MIC) of organisms for ≥40% of the dosing interval.²² In phase 3 clinical trials, a 1-hour infusion time has been used predominately.^23–26 In the Chastre et al²⁷ study, however, an extended infusion time of 4 hours was used for the treatment of patients with VAP. An extended infusion time theoretically optimizes the pharmacodynamic characteristics of the drug and may be more effective in maintaining the drug concentration above the MIC of less susceptible path-ogens.^22,28 Additional clinical data are necessary to further elucidate the true clinical relevance of this extended infusion time.

SPECTRUM OF ACTIVITY

Much like the other carbapenems, doripenem has demonstrated a broad spectrum of antibacterial activity against a variety of clinically relevant pathogens, including gram-positive and gram-negative aerobic and anaerobic species.^10,29–34 Of particular interest is doripenem's appreciable activity against a variety of drug-resistant pathogens, including beta-lactamase-producing gram-negative species.^9,35–38 Jones et al³⁵ demonstrated that doripenem may possess improved in vitro activity against an array of extended-spectrum beta-lactamase- and AmpC-producing gram-negative bacilli (dori-penem MIC₉₀, 0.03–0.5 mcg/mL) compared with the other carbapenems. The authors also noted that doripenem was the most active of the carbapenems against penicillin-resistant streptococci.³⁵ Improved in vitro activity has also been noted with doripenem against resistant gram-negative species (P aeruginosa, Burkholderia cepacia) isolated from patients with cystic fibrosis.^36,37 Although data such as these suggest superior in vitro potency for doripenem versus imipenem/cilastatin and meropenem, the clinical relevance of these in vitro findings is not clear.

One difference between doripenem and the other carbapenems is the improved activity noted in several in vitro studies for doripenem against P aeruginosa and Acinetobacter species.^32,34,35 Jones et al³⁵ demonstrated that, compared with other carbapenems, doripenem possesses superior in vitro activity against carbapenem-resistant, nonfermenting gram-negative bacilli. Pillar et al³⁴ also noted that, of the carbapenems, doripenem exhibits the greatest potency against P aeruginosa. These data suggest that doripenem may be an effective treatment option for patients who are at high risk of infection with resistant P aeruginosa (eg, patients at risk for nosocomial infections, patients with cystic fibrosis). However, increased MICs have been observed for doripenem against isolates of P aeruginosa that express the MDR phenotype, a trend that is also observed with imipenem/cilastatin and meropenem.³⁸ Some data have suggested that the combination of doripenem with an aminoglycoside may prevent the development of resistance when treating infections caused by P aeruginosa isolates with elevated carbapenem MICs.³⁹ Whether the improved in vitro activity of doripenem against P aeruginosa will translate into superior clinical outcomes for patients infected with such isolates requires further evaluation.

CLINICAL TRIALS

Complicated IAIs. Solomkin et al²⁶ presented pooled data from two phase 3 clinical trials.^24,40 IV doripenem 500 mg administered over 1 hour every 8 hours (n=486) was compared with meropenem 1 g administered as an IV bolus over 3 to 5 minutes every 8 hours (n=476) for the treatment of IAIs (Table 3). After $3 days (≥9 doses) of IV therapy, patients could switch to oral amoxicillin/clavulanate (875 mg/125 mg BID) for a total of 5 to 14 days of therapy. A follow-up assessment of clinical response was conducted 21 to 60 days after the completion of treatment. Pathogens isolated at baseline included Streptococcus species, Enterococcus faecalis, Enterobacteriaceae, E coli, K pneumoniae, P aeruginosa, Bacteroides species, and gram-positive anaerobes. Among microbiologically evaluable patients, those treated with doripenem demonstrated a clinical cure rate of 84.6% versus 84.1% among meropenem-treated patients (treatment difference, 0.5%; 95% CI, –5.5% to 6.4%). In the microbiological mITT population, doripenem-treated patients demonstrated a clinical cure rate of 76.2% versus 77.3% among meropenem-treated patients (treatment difference, –1.1%; 95% CI, –7.4% to 5.1%).

Nosocomial pneumonia and early-onset VAP. Rea-Neto et al²⁵ conducted a large, randomized, open-label, phase 3 study to evaluate the efficacy of doripenem compared with piperacillin/tazobactam (PTZ) for the treatment of nosocomial pneumonia or early-onset VAP (onset <5 d) (Table 3). Patients (N=448 randomized) received either IV doripenem 500 mg administered over 1 hour every 8 hours or IV PTZ 4.5 g administered over 30 minutes every 6 hours; patients were allowed to switch to oral levofloxacin 750 mg/d after the completion of ≥72 hours of IV therapy. In the clinically evaluable population, clinical cure rates at 7 to 14 days after treatment were 81.3% for doripenem-treated patients and 79.8% for PTZ-treated patients (treatment difference, 1.5%; 95% CI, –9.1% to 12.1%). In the clinical mITT population, clinical cure rates were 69.5% for doripenem-treated patients and 64.1% for PTZ-treated patients (treatment difference, 5.4%; 95% CI, –4.1% to 14.8%). Resistance to dori-penem was noted less frequently than resistance to PTZ among strains of P aeruginosa (4% vs 27%) and K pneumoniae (0 vs 43%).