Antibiotic Pharmacokinetic-Pharmacodynamic (PK/PD) Modeling: The Clinical and Laboratory Standards Institute (CLSI) is an international organization that critically evaluates clinical, laboratory, and PK-PD information to establish interpretive criteria for antibiotic susceptibility tests. The CLSI sets “breakpoints” which are a set of rules that microbiologists use to tell clinicians if a particular antibiotic is likely to be effective against a particular pathogen. Most developed countries use CLSI’s rules and validated methodologies in their clinical microbiology laboratories. Breakpoints are typically set at the time a drug is developed. Over time, the pathogen develops new resistance mechanisms that may render the old breakpoints invalid. During my postdoctoral training, I hypothesized that the breakpoints for beta-lactam antibiotics had been compromised because of emerging resistance in Gram-negative bacteria. My laboratory developed a comprehensive program to re-evaluate breakpoints for several antibiotic classes against key Gram-negative bacteria. We found major discrepancies for beta-lactam and fluoroquinolone antibiotic classes. I presented these results to CLSI. This work helped lead to a revision of CLSI’s breakpoints for the cephalosporin antibiotic class. This policy change has major implications for clinical microbiology laboratories around the world. PK-PD models can also be used to design dosing regimens to ensure patients get the most of their antibiotics. In some clinical studies at local hospitals, my research collaborators and I have found that patients who received PK-PD based dosing experienced better health outcomes than patients who received traditional dosing. Antimicrobial stewardship teams across the country now use these articles as strong evidence to implement PK-PD based dosing at their own hospitals to improve safety and effectiveness for their patients.
- Burgess DS, Frei CR. Comparison of beta-lactam regimens for the treatment of gram-negative pulmonary infections in the intensive care unit based on pharmacokinetics/pharmacodynamics. J Antimicrob Chemother. 2005 Nov;56(5):893-8. PubMed PMID: 16162664.
- Frei CR, Wiederhold NP, Burgess DS. Antimicrobial breakpoints for gram-negative aerobic bacteria based on pharmacokinetic-pharmacodynamic models with Monte Carlo simulation. J Antimicrob Chemother. 2008 Mar;61(3):621-8. PubMed PMID: 18252694; PubMed Central PMCID: PMC2952740.
- Hughes DW, Frei CR, Maxwell PR, Green K, Patterson JE, Crawford GE, Lewis JS 2nd. Continuous versus intermittent infusion of oxacillin for treatment of infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2009 May;53(5):2014-9. PubMed PMID: 19258261; PubMed Central PMCID: PMC2681516.
- Akers KS, Cota JM, Frei CR, Chung KK, Mende K, Murray CK. Once-daily amikacin dosing in burn patients treated with continuous venovenous hemofiltration. Antimicrob Agents Chemother. 2011 Oct;55(10):4639-42. PubMed PMID: 21825289; PubMed Central PMCID: PMC3186982.
Clinical Epidemiology, Health Outcomes, and Comparative-Effectiveness Research: My laboratory studies national data from federal agencies like the AHRQ, CDC, DOD, and VHA to detect emerging diseases, describe changes in medication use patterns, and calculate the economic burden on our national economy. We also compare health outcomes for patients receiving two or more treatments for different health conditions in an effort to identify the most cost-effective treatments for U.S. residents. We were the first to determine that patients with healthcare-associated pneumonia (HCAP) do not experience better health outcomes when treated with antibiotic recommendations consistent with national clinical practice guidelines. This and other papers have led the organizations that produced those guidelines to reconsider how they define the HCAP population and the antibiotics they recommend for that population. We have also determined that statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors are associated with better health outcomes in pneumonia patients admitted to the hospital; that antibiotic use has decreased among children and adolescents, but has increased for older adults–especially broad-spectrum antibiotic use; and that some measures of patient retention in HIV expert care are better than others to predict health outcomes. These findings are useful to health care providers and public health organizations as they seek ways to optimize the health of their patients.
- Attridge RT, Frei CR, Restrepo MI, Lawson KA, Ryan L, Pugh MJ, Anzueto A, Mortensen EM. Guideline-concordant therapy and outcomes in healthcare-associated pneumonia. Eur Respir J. 2011 Oct;38(4):878-87. PubMed PMID: 21436359.
- Mortensen EM, Nakashima B, Cornell J, Copeland LA, Pugh MJ, Anzueto A, Good C, Restrepo MI, Downs JR, Frei CR, Fine MJ. Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. Clin Infect Dis. 2012 Dec;55(11):1466-73. PubMed PMID: 22918991; PubMed Central PMCID: PMC3491858.
- Lee GC, Reveles KR, Attridge RT, Lawson KA, Mansi IA, Lewis JS 2nd, Frei CR. Outpatient antibiotic prescribing in the United States: 2000 to 2010. BMC Med. 2014 Jun 11;12:96. PubMed PMID: 24916809; PubMed Central PMCID: PMC4066694.
- Reveles KR, Juday TR, Labreche MJ, Mortensen EM, Koeller JM, Seekins D, Oramasionwu CU, Bollinger M, Copeland LA, Jones X, Frei CR. Comparative value of four measures of retention in expert care in predicting clinical outcomes and health care utilization in HIV patients. PLoS One. 2015;10(3):e0120953. PubMed PMID: 25794182; PubMed Central PMCID: PMC4368570.
Community Based Participatory Research: I have built and led a multidisciplinary group of researchers and practitioners (part of a regional Practice Based Research Network [PBRN] of primary care practices) to conduct a series of prospective clinical and translational studies to improve the health of their patients with MRSA skin and soft tissue infections (SSTIs). Together, we have determined that MRSA SSTIs are highly prevalent in our PBRN. We have identified objective markers available at baseline that can be used to predict which patients are most likely to experience treatment failure and recurrence. We have also identified practice behaviors that are associated with worse patient outcomes and have educated providers to avoid these practices. We have also conducted whole genome sequencing of the MRSA isolates to investigate genetic markers that may be contributing to treatment failure and recurrence. Finally, we have begun to implement new practice-based interventions to combat high rates of treatment failure and recurrence in our local patient population. We have even partnered with a group of biomedical engineers to develop and patent a point-of-care testing device to be used in the clinic to rapidly identify the pathogenic bacteria and test an array of antibiotics to see which are most likely to result in a positive patient outcomes. We continue to publish important study findings from this rich collaboration to help other practitioners who are also facing high rates of treatment failure and recurrence in their MRSA SSTI patients.
- Forcade NA, Parchman ML, Jorgensen JH, Du LC, Nyren NR, Treviño LB, Peña J, Mann MW, Muñoz A, Treviño SB, Mortensen EM, Wickes BL, Pollock BH, Frei CR. Prevalence, severity, and treatment of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections in 10 medical clinics in Texas: a South Texas Ambulatory Research Network (STARNet) study. J Am Board Fam Med. 2011 Sep-Oct;24(5):543-50. PubMed PMID: 21900437; PubMed Central PMCID: PMC3258020.
- Forcade NA, Wiederhold NP, Ryan L, Talbert RL, Frei CR. Antibacterials as adjuncts to incision and drainage for adults with purulent methicillin-resistant Staphylococcus aureus (MRSA) skin infections. Drugs. 2012 Feb 12;72(3):339-51. PubMed PMID: 22316350.
- Labreche MJ, Lee GC, Attridge RT, Mortensen EM, Koeller J, Du LC, Nyren NR, Treviño LB, Treviño SB, Peña J, Mann MW, Muñoz A, Marcos Y, Rocha G, Koretsky S, Esparza S, Finnie M, Dallas SD, Parchman ML, Frei CR. Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections: a South Texas Ambulatory Research Network (STARNet) study. J Am Board Fam Med. 2013 Sep-Oct;26(5):508-17. PubMed PMID: 24004702; PubMed Central PMCID: PMC3890434.
- Lee GC, Long SW, Musser JM, Beres SB, Olsen RJ, Dallas SD, Nunez YO, Frei CR. Comparative whole genome sequencing of community-associated methicillin-resistant Staphylococcus aureus sequence type 8 from primary care clinics in a Texas community. Pharmacotherapy. 2015 Feb;35(2):220-8. PubMed PMID: 25644979.
Drug Safety: I and my colleagues study active duty military and veteran populations to determine if the medications they receive affect their military readiness or long-term health. We have created cohorts of ambulatory and hospitalized patients and have followed them for up to eight years. Some of our key findings include new information regarding an association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia and associations between statin exposure and the development of musculoskeletal conditions, arthropathies, injuries, connective tissue disease, diabetes mellitus, and diabetic complications.
- Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013 Jul 22;173(14):1-10. PubMed PMID: 23877079.
- Schmidt T, Battafarano DF, Mortensen EM, Frei CR, Mansi I. Frequency of development of connective tissue disease in statin-users versus nonusers. Am J Cardiol. 2013 Sep 15;112(6):883-8. PubMed PMID: 23764243.
- Mortensen EM, Halm EA, Pugh MJ, Copeland LA, Metersky M, Fine MJ, Johnson CS, Alvarez CA, Frei CR, Good C, Restrepo MI, Downs JR, Anzueto A. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014 Jun 4;311(21):2199-208. PubMed PMID: 24893087; PubMed Central PMCID: PMC4109266.
- Mansi I, Frei CR, Wang CP, Mortensen EM. Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults. J Gen Intern Med. 2015 Apr 28;PubMed PMID: 25917657.