Introduction: Update on the Appropriate Use of Meropenem for the Treatment of Serious Bacterial Infections

Challenges in the treatment of serious bacterial infections include the requirement for prompt initiation of appropriate antimicrobial therapy (therapy that is correct on the basis of available clinical, pharmacological, and microbiological data) to minimize morbidity and mortality. Delaying the initiation of appropriate therapy or initiating inappropriate therapy has been shown, in numerous studies of a variety of serious bacterial infections, to be associated with poor outcomes [1–3]. Challenges in the determination of appropriate antimicrobial therapy for serious bacterial infections include an increasing incidence of antimicrobial-resistant pathogens [4–11]. In addition, for most cases of serious bacterial infection, there is little time to determine the right treatment, as time to initiation of effective therapy is a strong predictor of mortality. Thus, initial treatment must be empirical; that is, it must be implemented before pathogen culture and susceptibility results can be obtained. The strategy of using broad-spectrum antimicrobials as initial empirical therapy, selected on the basis of local pathogen prevalence and resistance profiles and patient clinical characteristics and followed by streamlining of therapy after the causative pathogen is identified, increases the chances of providing appropriate therapy and decreases the duration of broad-spectrum antimicrobial exposure [12]. De-escalation of antimicrobial therapy may provide survival benefits [13], in addition to being an important factor for reducing the risk of development of resistance [14]. Pathogen mechanisms of resistance are numerous, and, as new agents are introduced, new mechanisms of resistance emerge. If not used judiciously, agents that are effective today may become ineffective in the future. For example, bacterial production of extended-spectrum β-lactamases and AmpC chromosomal β-lactamases has rendered several commonly used β-lactam antimicrobial agents, including third-generation cephalosporins, ineffective in the treatment of serious bacterial infections [15]. Therefore, it is necessary to be very careful in current approaches to antimicrobial therapy, so that patients with serious infections are not left without effective therapy. Surveillance studies provide important information that allows assessment of pathogen incidence and antimicrobial resistance at global, national, local, and even institutional levels. Surveillance data on antimicrobial use provide important information for developing dosing strategies to reduce the emergence of resistance. Routine surveillance is critical for establishing methods to control antimicrobial resistance and for assisting clinicians in making decisions regarding appropriate treatment on the basis of the MIC of an agent against a pathogen in vitro. However, surveillance data are just one consideration; they provide no indication of the dose likely to be effective for a patient. Because the efficacy of an antimicrobial agent is dependent on its pharmacokinetic and pharmacodynamic properties, these unique properties may be exploited to optimize therapy. The approach of integrating mathematical modeling procedures that simulate population pharmacokinetics and surveillance data to determine an agent's pharmacodynamic profile is now being used to design rational antimicrobial dosing strategies [16]. Meropenem, a member of the carbapenem family, is a broad-spectrum β-lactam antimicrobial indicated for the treatment of complicated skin and skin-structure infections, serious intra-abdominal infections, and bacterial meningitis (when caused by susceptible isolates) in children aged ⩾3 months [17]. As reviewed in the article by Mohr in this supplement [18], meropenem has excellent efficacy in these applications and has also shown efficacy in clinical trials of initial empirical therapy for nosocomial pneumonia. Clinical trial data also indicate that meropenem is well tolerated, with adverse-event profiles similar to those of its comparators, in a variety of patient populations. Meropenem exhibits time-dependent bactericidal activity; therefore, for efficacy, drug concentrations must be maintained above the MIC for an adequate percentage of time. As discussed in the article by Nicolau in this supplement [19], meropenem has shown a high probability of attaining its bactericidal and bacteriostatic pharmacodynamic targets in numerous applications, with standard dosing regimens [20, 21]. The first 3 articles in this supplement, written by Kollef [22], Paterson [23], and Masterton [24], provide the rationale and evidence for the use of broad-spectrum antimicrobials as initial empirical treatment of serious bacterial infections, outline the growing problem of antimicrobial resistance and the need to optimize current therapy, and discuss the importance and future of antimicrobial surveillance studies in obtaining information essential for effective treatment and minimizing resistance. The last 2 articles, written by Nicolau [19] and Mohr [18], focus specifically on meropenem and provide a review of its pharmacokinetic and pharmacodynamic properties and its efficacy and tolerability. In accordance with the policy of judicious use of antimicrobials, meropenem is reserved for serious bacterial infections; its use as initial empirical therapy should be implemented only after consideration of local surveillance data and patient characteristics, and therapy should be narrowed after culture and susceptibility results become available [15, 25]. Careful use of this valuable agent, and others like it, in the treatment of serious bacterial infections should be a priority, so that resistance is kept to a minimum. I thank Stephanie M. Leinbach, who provided freelance medical writing support, and Judy E. Fallon from Scientific Connexions, who provided editing assistance, both funded by AstraZeneca. >Financial support. M.H.K. received financial compensation from AstraZeneca for his services as guest editor of this supplement. >Supplement sponsorship. This article was published as part of a supplement entitled “Update on the Appropriate Use of Meropenem for the Treatment of Serious Bacterial Infections,” sponsored by AstraZeneca LP. >Potential conflicts of interest. M.H.K. is on the speakers' bureau for Pfizer, Merck, Johnson & Johnson, and AstraZeneca; has received recent research funding from Pfizer and Bard Medical; has received grants from Merck, AstraZeneca, and Pfizer; and is a consultant to Bard Medical.