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Anti-infective Dosing in Special Populations

      In the current era, the buzzword personalized medicine is used endlessly to indicate our ongoing efforts to tailor therapy for the best patient outcomes. Most often, these discussions involve genetic studies that lead to the stratification of therapies for cancer, heart disease, and other conditions.
      • Salari K.
      • Watkins H.
      • Ashley E.A.
      Personalized medicine: hope or hype?.
      Despite the frequency of the use of this buzzword, the direct application of these genetic tests in the everyday practice of medicine is still uncommon. A much more practically relevant topic is how different physiologic or developmental states impact the effectiveness of commonly used drugs in different patients. The inherent differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties between a healthy adult and an infant, a pregnant woman, a patient with severe burns or one with morbid obesity will have a significant influence on the efficacy of any drug. While the principles could apply in any clinical scenario, for this Infectious Diseases Specialty Update in Clinical Therapeutics, we have invited experts to offer discussions of anti-infective dosing in special populations.
      The Update opens with an overview of important principles of PK and PD by Dr. Onufrak et al.
      • Onufrak N.J.
      • Forrest A.
      • Gonzalez D.
      Pharmacokinetic and pharmacodynamic principles of anti-infective dosing.
      The discussion provides the context and background for the rest of the articles. A statement they make in the summary rings true: "An appreciation of the PK/PD determinants of a given antibiotic can foster more rational and individualized dosing regimens, improving patient outcomes while simultaneously limiting the spread of resistance."
      The next several articles all discuss various aspects of anti-infective dosing in infants and children. Children under 18 years make up about 25% of the US population (2010 Census data), and the percentage is even higher in other parts of the world. Because of the rapid growth and development that occur in the first several years of life, this broad group of patients underscores the importance of a detailed understanding of PK/PD. The first article is by Drs. Johnson and Laughon
      • Johnson J.K.
      • Laughon M.M.
      Antimicrobial agent dosing in infants.
      and focuses on the premature and full term infants. This article is followed by a discussion from Dr. Parker et al
      • Dorofaeff T.
      • Bandini R.M.
      • Lipman J.
      • et al.
      Uncertainty in antibiotic dosing in critically ill neonate and paediatric patients: can microsampling provide the answers?.
      on methods of improved dosing in critically ill infants and children. When they are critically ill, many infants and children, and some adults, will require extracorporeal membrane oxygenation (ECMO). Dr. Sherwin et al
      • Sherwin J.
      • Heath T.
      • Watt K.
      Pharmacokinetics and dosing of anti-infective drugs in patients on extracorporeal membrane oxygenation: a review of the current literature.
      offer a discussion about how ECMO changes the metabolism and distribution of anti-infective agents. In an original manuscript included in this special issue, Dr. Zimmerman et al
      • Zimmerman K.
      • Putera M.
      • Hornik C.P.
      • et al.
      Exposure matching of pediatric anti-infective drugs: review of drugs submitted to the Food and Drug Administration for pediatric approval.
      offer a discussion of how the US Food and Drug Administration (FDA) evaluates anti-infective medications for use in pediatric patients and the principle of exposure matching. They note in their discussion: "Criteria for exposure matching between children and adults for pediatric drug approvals have not been defined in the United States… . Sponsors define their own targets for exposure matching for each drug product. The result of this method is variability in the exposure measure of interest and variability in acceptable parameters for exposure matching."
      The next few articles involve several conditions that are often temporary in nature but that dramatically alter the requirements for anti-infective dosing. Pregnancy is a condition that affects what is essentially half the world’s population at some point, and Dr. Patil
      • Patil A.S.
      • Sheng J.S.
      • Dotters-Katz S.K.
      • et al.
      Principles of anti-infective dosing in pregnancy.
      reviews the salient changes in pregnancy and the dosing changes required. This piece is particularly timely as it follows up on changes made by the FDA in how drugs are labeled to address the inherent differences during pregnancy.
      US Food and Drug Administration
      Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling.
      Severe burn injuries dramatically change a person’s physiology, and Dr. Akers et al
      • Cota J.M.
      • Fakhri Ravari A.
      • Rowan M.P.
      • et al.
      Intravenous antibiotic and antifungal agent pharmacokinetic-pharmacodynamic dosing in adult patients with severe burn injury.
      discuss commonly used strategies for optimal anti-infective treatment in burn patients.
      Finally, with obesity being a condition with a prevalence of over 30% among the US population, knowledge of proper anti-infective dosing in obese patients is required for all clinicians.
      • May A.L.
      • Freedman D.
      • Sherry B.
      • Blanck H.M.
      Obesity—United States, 1999-2010.
      Since the scope of the discussion could be overwhelming, Dr. Pai
      • Pai M.P.
      Anti-infective dosing for obese adult patients: a focus on newer drugs to treat methicillin resistant Staphylococcus aureus acute bacterial skin and skin structure infections.
      offers a focused discussion of a highly relevant situation in obese patients. Methicillin-resistant Staphylococcus aureus (MRSA) is a superinfection common with influenza virus, and it is well known that the 2009 H1N1 influenza caused disproportionate morbidity and mortality in obese patients.
      • Louie J.K.
      • Acosta M.
      • Samuel M.C.
      • et al.
      A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1).
      • Shah N.S.
      • Greenberg J.A.
      • McNulty M.C.
      • et al.
      Bacterial and viral co-infections complicating severe influenza: incidence and impact among 507 U.S. patients, 2013-14.
      We appreciate the contributions of all the authors in this Specialty Update. These articles offer a wealth of information for our readers that will help them take a more "personalized" approach with their patients.
      Finally, we end on a sad note. One of the co-authors in this Update, Dr. Matthew Rowan, was among those killed in a hot air balloon accident in central Texas on July 30, 2016. Our deepest sympathies go out to Dr. Rowan’s family and friends as they deal with this tragedy. This event is yet another reminder that we are all more connected than we think and that we should treasure each and every day.

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