Invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA), particularly those involving persistent bacteraemia, necrotizing pneumonia, osteomyelitis and other deep-seated sites of infections, are associated with high mortality and are often difficult to treat. The response to treatment of severe MRSA infection with currently available antibiotics active against MRSA is often unsatisfactory, leading some physicians to resort to combination antibiotic therapy. Now, with the emergence of community-associated MRSA (CA-MRSA) clones that display enhanced virulence potentially related to up-regulated toxin production, the use of adjuvant protein synthesis-inhibiting antibiotics to reduce toxin production also has been advocated by some experts. In this review, we discuss the limitations of antibiotics currently available for the treatment of serious invasive MRSA infections and review the existing literature that examines the potential role of combination therapy in these infections.

Traditionally, physicians have not used cefepime (a fourth-generation cephalosporin with greater stability against β-lactamases) or β-lactam/β-lactamase inhibitors (BLBLIs) for infections caused by bacteria (generally Escherichia coli and Klebsiella species) that produce an extended-spectrum β-lactamase (ESBL). Many microbiology laboratories have historically labelled these ESBL-producing organisms as resistant to all cephalosporins regardless of their MIC. The recommendation to eliminate ESBL identification started with EUCAST in 2009, followed by CLSI in 2010. As a consequence, many ESBL-producing organisms that were previously labelled as resistant to all cephalosporins may be reclassified as susceptible to some (particularly cefepime), depending on their MICs. Because there are limited treatment options against ESBL-producing organisms, there is growing interest in using cefepime and BLBLIs. In this review, we examine the clinical outcomes of therapy directed against ESBL-producing Enterobacteriaceae and the pharmacokinetics/pharmacodynamics of cefepime and BLBLIs to construct a clinical framework for how physicians can best employ these carbapenem-sparing alternatives for the treatment of infections caused by ESBL-producing Enterobacteriaceae. We conclude that standard-dose cefepime is a reasonable option for the definitive therapy of invasive infections resulting from ESBL-producing E. coli and Klebsiella species when the MIC for the organism is ≤ 2 mg/L (CLSI) or ≤ 1 mg/L (EUCAST), although higher doses may be considered for MICs in the 4-8 mg/L range. Piperacillin/tazobactam is also a reasonable option when the MIC is ≤ 16 mg/L.

Given current challenges in antimicrobial resistance and drug development, infectious diseases clinicians must rely on their own ingenuity to effectively treat infections while preserving the current antimicrobial armamentarium. An understanding of pharmacokinetics (PK), pharmacodynamics (PD), antimicrobial susceptibility testing (AST), and how these concepts relate, is essential to this task. In this review, we discuss how and why PK-PD impacts AST and the way infectious diseases are being treated, with a particular focus on vancomycin for methicillin-resistant Staphylococcus aureus, penicillin for Streptococcus pneumoniae, and an update on cephalosporins for Enterobacteriaceae. Finally, we address how new ideas to exploit PK-PD can promote innovative study design and bring about more rapid regulatory review of new antimicrobials.

The simplified ASP ratio is derived from a parsimonious model that incorporates disease burden through patient-level risk adjustment and better informs stewardship assessment. This may allow for improved comparison of antibiotic use between healthcare facilities.

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