Early appropriate therapy of Gram-positive bloodstream infections: the conservative use of new drugs

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Abstract

Among the Gram-positive organisms, meticillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium represent the biggest therapeutic hurdles. The evolution of MRSA exemplifies the genetic adaptation of an organism into a first-class multidrug-resistant pathogen. Glycopeptides such as vancomycin have been the treatment of choice for MRSA, but poor outcomes have frequently been reported, particularly among isolates with higher minimum inhibitory concentrations (MICs) within the susceptible range (≤2 mg/L). Further more, vancomycin's limitations as an antibacterial agent include slow bactericidal activity and relatively poor tissue penetration. Inadequate dosing may, however, contribute to vancomycin's poor performance; the standard recommendation for trough concentrations of 5–10 mg/L is inadequate for serious infections such as bacteraemia and endocarditis. Trough levels of 15–20 mg/L are probably necessary; however they are often associated with increased nephrotoxicity. Despite the recent dramatic reduction in antibiotic research by pharmaceutical companies, a few compounds have been developed to treat Gram-positive infections. Quinupristin–dalfopristin, although shown to have in vitro activity against MRSA, is not approved by the US Food and Drug Administration for the treatment of MRSA, and cannot be recommended for the treatment of S. aureus bacteraemia, except under exceptional circumstances. Although linezolid and tigecycline may be useful in specific situations, they cannot be routinely recommended for the treatment of MRSA bacteraemia because of safety concerns and very limited available clinical data. Daptomycin has recently been proven to be effective and well tolerated for meticillin-sensitive S. aureus and MRSA bacteraemia, including right-sided endocarditis.

Introduction

Infections caused by multidrug-resistant microorganisms present daily challenges to infectious diseases physicians and their patients. Bacteria are champions of evolution, and several have adapted to a point where they pose a serious clinical challenge for humans. These bacteria have recently been described as the ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., to emphasize that they currently cause most hospital infections and effectively escape the effects of antibacterial drugs [1]. It is difficult to imagine undertaking today's surgical procedures, transplantations, cancer chemotherapy or the care of critically ill or HIV-infected patients without effective antimicrobial agents.

Despite the increasing importance of Gram-positive bacterial infections [2, 3], and in particular the clinical problems related to meticillin-resistant S. aureus (MRSA) bacteraemia [4, 5, 6], there is no international consensus on the diagnosis and management of Gram-positive bloodstream infections (BSI). In a recent survey of >24 000 cases of nosocomial bacteraemia in 47 US hospitals, Gram-positive pathogens were responsible for 65% of infections, the most common organisms being coagulase-negative staphylococci (CoNS), S. aureus and enterococci [7]. In the present paper the focus is restricted to the treatment of infections caused by S. aureus.

Despite its sustained in vitro microbiological inhibitory activity, clinicians now question the continued utility of vancomycin for MRSA infections [8, 9]. Within the past 5 years, multiple reports have described MRSA strains with vancomycin minimum inhibitory concentrations (MIC) at the high end of the Clinical and Laboratory Standards Institute (CLSI) susceptibility range (2 mg/L) [8, 10]. Although data suggest that vancomycin has reduced activity against MRSA infections when MICs are at the high end of the susceptibility range [11, 12, 13, 14, 15], it is important to realize the important limitations of the clinical laboratory in detecting reduced susceptibility and resistance to vancomycin [16].

Furthermore, vancomycin's limitations as an antibacterial agent include slow bactericidal activity and relatively poor tissue penetration. Inadequate dosing may, however, contribute to vancomycin's poor performance; the standard recommendation for trough concentrations of 5–10 mg/L is inadequate for serious infections such as bacteraemia and endocarditis. Trough levels of 15–20 mg/L are probably necessary; however they are often associated with increased nephrotoxicity [17, 18].

Treatment guidelines for bacteraemia are primarily based on specific sites of associated infections, such as infective endocarditis (IE) [19, 20, 21, 22] and catheter-related infections [23]. The selection of antimicrobial agents for S. aureus bacteraemia is typically made on the basis of a combination of antibiotic susceptibility, local formulary restrictions, clinical experience and often less-than-rigorous clinical trial data. Although no clinical trials suggest the superiority of vancomycin over any comparator, some have provided evidence of its inferiority. Consideration should therefore be given to the use of alternative agents in the treatment of serious S. aureus infections [24].

Section snippets

New drugs

Despite the recent dramatic reduction in antibiotic research by pharmaceutical companies, several compounds have been developed to treat Gram-positive infections, including quinupristin– dalfopristin, linezolid, daptomycin and tigecycline. Although these agents are extremely valuable in the fight against MRSA, each has limitations. New lipoglycopeptides (telavancin, dalbavancin and oritavancin) are in an advanced phase of clinical development. Similarly, new broad-spectrum cephalosporins active

Discussion

The treatment of serious drug-resistant Gram-positive infections remains a challenge, despite the development of several new antibiotics over the past 10 years. Vancomycin, still the most frequently chosen antibiotic for the treatment of severe MRSA infections, has become a suboptimal therapy in selected clinical settings. However, clinical trials have consistently failed to demonstrate superiority for the new antibiotics, despite promising antimicrobial profiles, and clinicians have begun

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