JPIDS Article Review: July 2016
Written by: Louise Vaz, MD MPH Assistant Professor, Oregon Health & Science University
As a result of growing antimicrobial resistance worldwide, the promotion of judicious use of antibiotics (1) has become increasingly important. In the health care setting, antibiotic stewardship programs (ASPs) aim to achieve excellent clinical outcomes while at the same time minimize toxicity, reduce costs, and decrease unnecessary exposure to broad spectrum antibiotics, thus limiting selection for antimicrobial resistant strains (2,3).
At the same time, exciting advances in detecting antimicrobial resistant pathogens from clinical specimens are in development. The manner by which hospitals and microbiology labs are able to use this technology to drive patient care is highlighted by the study by Malcolmson and colleagues, reported in the JPIDS early web release on June 23rd (4).
Malcolmson et al report their experience in optimizing antimicrobial therapy at their institution after implementation of a new Matrix — Assisted Laser Desorption and Ionization Time of Flight (MALDI-TOF) mass spectrometry system. A MALDI-TOF mass spectrometry identifies microorganisms down to subspecies level. In simple terms, bacteria or yeast are selected from a culture plate or broth cultures and transferred to a target plate that lyses the organisms with solvents. The lysate is then run through the MALDI-TOF, which compares the subsequent spectral profiles of a number of bacterial components to those in a database for organism identification. Compared to traditional methods, which rely on bacterial growth characteristics and phenotypic criteria in biochemical reactions, long incubation times, and intensive personnel time, the MALDI-TOF can be an accurate, rapid, and inexpensive way to identify bacteria, fungi, and mycobacteria. Limitations of MALDI-TOF reflect the accuracy of identification with a small inoculum, the need to run susceptibilities separately, and the difficulty of separating closely related species (such asS.pneumoniae, S. mitis, and S. oralis). Within the last five years, MALDI-TOF has emerged as an important diagnostic tool in clinical microbiological laboratories (5–7).
Malcolmson’s paper capitalizes on the introduction of this technology at their institution to retrospectively capture outcomes of a new MALDI-TOF system for early identification of positive blood cultures. This coincided with the hospital’s new ASP. Using a quasi-experimental design, the pre-period was defined as October 2009 — July 2010, when positive cultures from the BACTEC machine were gram stained and sub-cultured for identification and occurred prior to the institution of an ASP. Results were entered into a lab system, with fax and phone call to the ordering unit or physician. This was compared to the post period between October 2013 to July 2014, when both the MALDITOF and ASP program were initiated. In the post period, an aliquot from the positive blood culture was run through their MALDI-TOF with results compared to the gram stain followed by the same notification system. The ASP included prospective audit and feedback by a clinical pharmacist who checked cultures and susceptibilities daily and communicated with the treating team about the management plan.
Charts were reviewed for patients with a positive blood culture for bacteria or yeast. Patients with contaminants and those with blood cultures positive prior to their admission were excluded. The primary outcome of interest was time to optimal therapy, defined as the number of hours from blood culture collection to time of antimicrobial with the narrowest effective spectrum. The study also measured the following secondary outcomes: time to effective therapy (defined in hours as the time from collection of the blood culture to time of first antimicrobial agent with known susceptibility), 30 day all-cause mortality, length of stay, readmission, and time to pathogen identification among others. The authors used descriptive statistics to describe outcomes during the two periods.
Results included 100 episodes of blood stream infections in the pre period and 121 in the post period. Minor differences were noted between the two periods but otherwise baseline demographics were similar. The main outcome of interest, time to optimal (narrowest) therapy, showed a significant reduction in the post period from 77 to 54.2 hours (p<0.001). While not statistically significant, time to effective therapy trended to improvement from 2.6 hours to 1.6 hours p=0.058. Time to organism identification was dramatically reduced from 43.7 hours to 18.8 hours (p<0.001). No other differences in outcomes were noted. In their subgroup analysis, gram negative bacteremia demonstrated statistically significant decreases in both time to effective and optimal therapy (2.0 to 0.7 hours and from 146.8 hours to 48 hours, p<0.001 respectively). Multidrug resistant gram negatives were identified more quickly (41.3 vs. 16.7 hours) and time to optimal therapy (149.5 hours vs. 16.0 hours) was decreased (p=0.002). ASP interventions included discontinuation of antimicrobials, tailoring to culture and susceptibility, and optimization of dose based on information garnered from the MALDI-TOF results. Specifically, ASP made 15 recommendations to broaden and 36 recommendations to narrow therapy. Other outcomes, including mortality, were not significantly different. Readmission numbers were very low across the study and C.difficile rates were not different in the periods.
While a single center study, Malcolmson et al demonstrated that the combined approach of an improved detection system and an effective ASP decreased time to optimal and, sometimes, effective antimicrobial therapy. This was particularly apparent for gram negative infections. It would have been interesting to quantify the added benefit of the ASP with these new technology platforms, but this could not be captured as both interventions were implemented nearly simultaneously. Additionally, the ASP in this institution did not operate round the clock daily, which could reflect additional lost benefits in time to optimal therapy.
With quicker and more accurate systems of microbial identification from various clinical sources, blood, tissue, CSF, etc. on the horizon, we may be better able to reduce unnecessary broad spectrum antibiotics and streamline empiric-to appropriate-antimicrobials more quickly. The MALDI-TOF system continues to be refined and other platforms, including those that are molecular based, such as Verigene, are already being utilized (6,8,9). Growing numbers of antimicrobial stewardship programs across the country are demonstrating value by reducing antimicrobial use and improving quality of care (2,3). Enhanced technologies that allow for rapid identification of pathogens could have enormous promise within these programs. The sooner we know the organism and susceptibility, the faster informed interventions can take place.
Spellberg B, Blaser M, Guidos RJ, et al. Combating antimicrobial resistance: policy recommendations to save lives. CID. 2011;52 Suppl 5(suppl 5):S397–428.
IDSA. New Antibiotic Stewardship Guidelines Focus on Practical Advice for Implementation. Webpage. 2016.
Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. CID. 2016;62(10):e51–77.
Malcolmson CNKHSKNSJTPRA. Impact of Matrix-Assisted Laser Desorption and Ionization Time-of-Flight and Antimicrobial Stewardship Intervention on Treatment of Bloodstream Infections in Hospitalized Children. JPIDS. 2016;June 23(epub ahead of print).
Murray PR. What is new in clinical microbiology-microbial identification by MALDI-TOF mass spectrometry: a paper from the 2011 William Beaumont Hospital Symposium on molecular pathology. J Mol Diagn. 2012;14(5):419–23.
Singhal N, Kumar M, Kanaujia PK, Virdi JS. MALDI-TOF mass spectrometry: an emerging technology for microbial identification and diagnosis. Front Microbiol. 2015;6:791.
Bailey D, Diamandis EP, Greub G, Poutanen SM, Christensen JJ, Kostrzew M. Use of MALDI-TOF for diagnosis of microbial infections. Clin Chem. 2013;59(10):1435–41.
Beal SG, Ciurca J, Smith G, et al. Evaluation of the nanosphere verigene gram-positive blood culture assay with the VersaTREK blood culture system and assessment of possible impact on selected patients. J Clin Microbiol. 2013;51(12):3988–92
Bork JT, Leekha S, Heil EL, Zhao L, Badamas R, Johnson JK. Rapid testing using the Verigene Gram-negative blood culture nucleic acid test in combination with antimicrobial stewardship intervention against Gram-negative bacteremia. Antimicrob Agents Chemother. 2015;59(3):1588–95.