Editorial Commentary: Saving Lives With Optimal Antimicrobial Chemotherapy

Abstract

The introduction of antimicrobial chemotherapy was an unprecedented advance in the practice of medicine. Previously fatal infections became treatable and antimicrobials were the agents of that salvage of life. In the more modern era, these agents also became the drugs that were permissive for many of the other modern medical miracles that we currently enjoy. The ability to treat serious infections in neutropenic cancer patients allowed the use of intensive oncologic chemotherapy. In the same vein, immunosuppressive therapy for organ and bone marrow transplants are made possible by antimicrobial therapy, as has the routine use of interventions that cross natural anatomic boundaries. In the early days of antimicrobial therapy, pioneers such as Harry Eagle recognized that certain administration profiles of drug prompted better therapeutic effect. This was demonstrated in a landmark paper published in the New England Journal of Medicine [1]. Certain agents such as penicillin had a better therapeutic effect when administered on very short administration intervals, whereas drugs such as the tetracyclines had antimicrobial effects that were somewhat independent of administration schedule. Unfortunately much of this information became lost in the 1960s and 1970s. In the late 1980s and early 1990s, these principles were rediscovered by the laboratory of William Craig [2–4]. These studies linked the effect of different antimicrobial classes, doses, and schedules to the reduction in colony-forming units (CFUs) in murine thigh or pneumonia models. Shortly thereafter, the burgeoning science of pharmacodynamics and pharmacometrics allowed identification of relationships between drug exposure indexed to the minimum inhibitory concentration (MIC) of the infecting pathogen and clinical and/ or microbiological outcomes [5–7]. The first study was a retrospective evaluation, but the last 2 were prospectively designed with analysis plans filed with the Food and Drug Administration (FDA). Such studies demonstrated conclusively that it was relatively straightforward to derive exposure-response relationships in the midst of clinical trials, employing a number of different mathematical techniques. The next step was to demonstrate the link between the animal model findings and the clinical trial pharmacodynamics relationships. Ambrose and colleagues [8] examined outcomes from clinical trials relative to the effect breakpoints determined from murine pharmacodynamic studies. They demonstrated a strong concordance between the preclinical and clinical pharmacodynamic studies for a number of different antimicrobial classes. Consequently, we can say that another brick was laid in the edifice of antimicrobial dynamics. While these data are convincing, it is also important to demonstrate that attainment of the “correct” antimicrobial targets has an impact on endpoints other than traditional clinical and microbiological outcomes in “real world” clinical practice settings. The clinical benefits of prolonged β-lactam infusion among critically ill patients were highlighted by the study performed at Albany Medical Center Hospital by Lodise and colleagues. Based on the results of a Monte Carlo simulation, prolonged infusion of piperacillin-tazobactam (3.375 g administered over a 4-hour period every 8 hours) was adopted as the standard hospital-wide piperacillin-tazobactam dosing scheme at their institution in February 2002. To evaluate the real-world effectiveness of this automatic dose substitution program, 14-day mortality and hospital length of stay after culture collection were Received 3 September 2012; accepted 11 September 2012; electronically published 16 October 2012. Correspondence: G. L. Drusano, MD, Professor and Director, Institute for Therapeutic Innovation, Department of Medicine, University of Florida, 6550 Sanger Boulevard, Lake Nona, FL, 32827 (gdrusano@ufl.edu). Clinical Infectious Diseases 2013;56(2):245–7 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cis863