Abstract
This symposium on nosocomial infections, antimicrobial resistance and the benefits of doripenem in this setting was held in Madrid, Spain, on 7 October 2009, and was supported by Janssen-Cilag. The topic was presented under an interdisciplinary approach by different international experts in the field.
Nosocomial infections, particularly in critical settings, are associated with a high risk of morbidity and mortality. Moreover, the increase in antimicrobial resistance reflects the loss of efficacy of current therapies and the need for new therapies that allow successful treatment of nosocomial infections. In this context, doripenem, a new carbapenem, is an effective and safe approach to treat nosocomial infections.
José Antonio Buron presented the clinical development of doripenem. The continuous increase of antibiotic-resistant bacteria, particularly Gram-negatives, in most European countries and the current difficulties found in the treatment of some bacteria such as Pseudomonas aeruginosa, have created the need to develop new and more effective antibiotics. Doripenem is an antibiotic belonging to the carbapenem class, indicated for the treatment of nosocomial pneumonia (including ventilator-associated pneumonia), complicated intra-abdominal infections and complicated urinary tract infections. Its clinical use was approved by the European Medicines Agency in July 2008. The clinical development of doripenem consisted of six randomized and noninferiority Phase III clinical trials. DORI-05 and DORI-06 trials showed that in more than 1200 patients with complicated urinary tract infections, doripenem 500 mg intravenously every 8 h (60-min infusion) was noninferior to levofloxacin 250 mg daily. DORI-07 and DORI-08 trials included 692 patients and demonstrated that doripenem (same dosing regimen) was noninferior to meropenem (1 g every 8 h) in the treatment of complicated intra-abdominal infections.
DORI-09 was a multicenter, randomized, comparative study of the safety and efficacy of doripenem and piperacillin/tazobactam in nonventilated subjects with nosocomial pneumonia and subjects with early onset ventilator-associated pneumonia. DORI-10 was a multicenter, randomized, comparative study of the safety and efficacy of doripenem and imipenem in subjects with early onset and late-onset ventilator-associated pneumonia. In DORI-09, doripenem was dosed at 500 mg in a 1-h infusion every 8 h whereas a 4-h infusion of the same dosage was used in DORI-10. The prolonged infusion was employed in DORI-10 to enhance antibacterial coverage for the less-susceptible pathogens frequently encountered in ventilator-associated pneumonia. Buron concluded that doripenem is a new carbapenem with broad-spectrum activity against clinically important pathogens.
Gian Maria Rossolini updated the current data regarding antimicrobial resistance. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci rates have leveled off or are decreasing in several European countries. However, resistant Gram-negatives are increasing in most European countries Citation[1]. As a result, the treatment of some bacteria such as Enterobacteriaceae, P. aeruginosa or Acinetobacter baumannii is challenging. Group 2 carbapenems (imipenem, meropenem and doripenem) are considered to have the broadest activity among β-lactams, which makes them attractive for empiric treatment of serious infections caused by difficult-to-treat pathogens.
Rossolini summarized the design and results of the COMPACT (Comparative Activity of Carbapenem Testing) study. The COMPACT study was performed to evaluate the in vitro activity of doripenem, imipenem and meropenem against recent clinical isolates of selected Gram-negatives, and to compare the local pathogen susceptibility to doripenem, imipenem and meropenem and compare this with the general susceptibility patterns across Europe (12 countries participated). For this purpose, 3337 isolates of P. aeruginosa (49%), Enterobacteriaceae (42%), Acinetobacter spp. (8%) and other Gram-negative nonfermenters (1%) were collected from patients with nosocomial pneumonia, including ventilator-associated pneumonia (40%), bloodstream infections (38%) and complicated intra-abdominal infections (22%). The main results of this study showed that doripenem had good activity against nosocomial pathogens. Doripenem was more active than imipenem and at least as active as meropenem against recent isolates of Gram-negatives. Moreover, doripenem was the most active carbapenem against P. aeruginosa.
Due to the limited number of antibiotics available, the future of antibiotics will be determined by considering their pharmacokinetic (PK) and pharmacodynamic (PD) properties in order to optimize the antimicrobial treatment. Regarding this matter, Santiago Grau Cerrato reviewed the pharmacological characteristics of the main antimicrobial agents.
From a pharmacological point of view, the most important predictor for an antibiotic is the PK/PD profile. To assess the PK/PD profile, it is necessary to know the MIC as well as the PK behavior of the antibiotic.
Time above MIC (T>MIC) for free drug concentrations is an important PK/PD parameter correlating with the efficacy of β-lactam antibiotics. Carbapenems need a lower percentage to achieve T>MIC (∼40%) when compared with penicillins and cephalosporins Citation[2]. A recent study that evaluated the MICs of five carbapenem antibiotics (imipenem, meropenem, biapenem, doripenem and panipenem) against 100 P. aeruginosa strains showed that the probability of achieving 25% T greater than MIC and 40% T greater than MIC against P. aeruginosa with any dosage regimen was higher with doripenem than with any other carbapenem tested Citation[3].
In another study, the Monte Carlo simulation was performed in plasma and urine samples of patients treated with doripenem using 1-h or 4-h infusion. The results showed that against microorganisms with higher MICs, extending time of infusion was more effective than dose increase Citation[4]. Thus, it has been suggested that the best therapeutic approach with doripenem is 1-h infusion in the case of microorganisms with a MIC less than 1 µg/ml and 4-h infusion for microorganisms with a MIC greater than 1 µg/ml Citation[5]. The higher stability of doripenem in comparison with other carbapenems allows both regimens of treatment. This is a great advantage for the treatment of complicated pathogens. Therefore, doripenem has some pharmacological benefits over other antibacterials, including other carbapenems, which may translate into better management of the patient.
The last presentation was given by Jordi Rello. The different therapeutic strategies of nosocomial pneumonia in the critical care setting were discussed. Nosocomial pneumonia is the most common healthcare-acquired infection, contributing to death and increasing length of stay in hospital by 7–9 days Citation[6]. The treatment of these patients must be individualized according to suspected pathogens and susceptibility patterns, patients’ risk factors, comorbidities and PK/PD principles, among others, and should be continually revaluated. The key pathogens in this setting are P. aeruginosa, Acinetobacter baumannii and methicillin-resistant S. aureusCitation[7].
Carbapenems are indicated as initial therapy for late-onset nosocomial pneumonia and when multidrug-resistant pathogens are suspected. They are also indicated as initial therapy in nosocomial pneumonia for patients at risk for multidrug pathogens (recently hospitalized patients, and nursing home or long-term care patients) and as a second-line therapy after failure of other therapies Citation[7]. However, a recent meta-analysis that compared the efficacy and safety of carbapenems (meropenem and imipenem) with other β-lactams and fluoroquinolones for the empirical treatment of patients with hospital-acquired pneumonia showed that the efficacy of these carbapenems was suboptimal, particularly against P. aeruginosaCitation[8].
Doripenem has numerous advantages over other carbapenems: doripenem has enhanced activity against P. aeruginosa, a lower propensity for developing resistant P. aeruginosa, and a reduced potential for seizure development in experimental models. Moreover, it is more stable after reconstitution and has the ability to use extended intravenous infusions to maximize T above MIC. Furthermore, it is safer than other carbapenems, with a lower incidence of convulsions.
The DORI-09 and DORI-10 trials showed that in patients with nosocomial pneumonia, including ventilator-associated pneumonia, doripenem was clinically effective and therapeutically noninferior to piperacillin/tazobactam or imipenem. Doripenem was active in vitro against the vast majority of Gram-negative pathogens at baseline, including P. aeruginosa, Klebsiella pneumoniae and other Enterobacteriaceae, regardless of whether or not they were susceptible or resistant to piperacillin/tazobactam or imipenem. Moreover, doripenem was found to have less baseline resistance among serious Gram-negative pathogens compared with imipenem and piperacillin/tazobactam and less frequent emergence of resistant P. aeruginosa compared with imipenem. Doripenem was generally safe and well tolerated.
Rello concluded that doripenem is a new and potentially useful empiric therapy for nosocomial pneumonia, including ventilator-associated pneumonia.
Javier Garau concluded the symposium. In recent years there has been a progressive increase of resistant Gram-negative pathogens. The combination of different antibiotics with synergistic mechanisms of action may be useful for the management of multidrug-resistant Gram-negative infections. In critical patients, carbapenems at a high dose must be part of the therapeutic approach. In this context, doripenem has good activity against nosocomial pathogens, being more active than imipenem and at least as active as meropenem against recent isolates of Gram-negative pathogens. Moreover, doripenem is the most active carbapenem against P. aeruginosa.
The importance of clinical pharmacology is increasing. The higher stability of doripenem in comparison with other carbapenems allows the time of infusion to be increased, improving its efficacy. Like other β-lactams, doripenem is safe and well tolerated, with a lower frequency of convulsions when compared with other carbapenems. Finally, since doripenem reduces the length of hospital stay and the duration of mechanical ventilation, the use of doripenem is a cost-effective approach.
Financial & competing interests disclosure
This article was sponsored by Janssen-Cilag Spain. José Antonio Buron is an employee of Janssen-Cilag Spain. Gian Maria Rossolini, Santiago Grau Cerrato, Jordi Rello, Rafael Zaragoza and José Angel García Rodriguez have received personal compensation for activities (consulting, clinical research and presenting at conferences) with Janssen-Cilag Spain. Javier Garau is in receipt of research funding from AstraZeneca and has received honoraria or has been an advisor for Novartis, GlaxoSmithKline, Pfizer, Bayer, Astellas and Janssen-Cilag. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Writing assistance was utilized in the production of this manuscript and was provided by ContentEdNet and funded by Janssen-Cilag Spain.
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