Division of Infectious Diseases

Pharm To Exam Table: Dual Antiretroviral Therapy with Dolutegravir + Lamivudine

Pharm To Exam Table: Dual Antiretroviral Therapy with Dolutegravir + Lamivudine

Currently, triple therapy regimens constituted with a two nucleoside reverse transcriptase inhibitor backbone and anchored by an integrase inhibitor has been the standard treatment for HIV infection. However, these conventional therapies are being challenged due to their long-term side effects. Dual therapy regimens were recently introduced with the first comprising of dolutegravir (DTG)/rilpivirine (RPV). The combination was approved under the trade name JULUCA® in the setting of antiretroviral therapy (ART) switch cases for maintenance of viral suppression. Current trials are ongoing to support dual therapy for patients who are treatment naïve or experienced. DTG 50mg paired with lamivudine (3TC) 300mg has been introduced as a potential option for dual therapy. The agents of interest offer an array of advantages when compared to the conventional triple therapy.  DTG is a potent agent exhibiting a high genetic barrier to drug resistance and 3TC offers a complimentary agent with low toxicity. In addition, the potential for drug-drug interactions is minimal with DTG/3TC.

A number of studies have released data in which they assess the practicality of dual antiretroviral therapy with DTG/3TC.  Below, is a summary of such studies:

PADDLE Trial4: A pilot, non-blinded, non-randomized, non-parallel, 48 week trial in Argentina. This trial enrolled 20 patients that were naïve to ART, viral loads ranging from 5,000 to 100,000 copies/mL and CD4+ greater 200cells/mm3. The participants in this trial were primarily assessed to see the rate of success at achieving HIV levels of 50 copies/mL or less at 48 weeks. At 48 weeks, 18/20 (90%) patients reached the viral levels desired, including 4 patients with viral loads greater than 100,000 (albeit to protocol). Additionally, safety and efficacy of this dual therapy was analyzed in this trial. Only one protocol failure developed; however, participants achieved levels less than 50 copies/mL from Week 4-24 and developed no resistance to any of the agents.

ASPIRE Trial3: A pilot, open-label, randomized, parallel, multicenter, 48-week clinical trial that enrolled 90 treatment experienced patients. The HIV RNA viral loads ranged from undetectable to less than 50 copies/mL and CD4+ greater than 200/mm3. The primary objective of this study was to assess the possibility of using DTG/3TC as maintenance therapy, compare the rate of failure in both arms, and establish non-inferiority to conventional ART. The rate of failure was similar in both arms with 3/44 (6.8%) patients in DTG/3TC and 3/45 (6.7%) in the triple ART arm developing protocol defined failure. Participants with treatment failure were further examined and found to have no drug mutations that would confer resistance to treatment.

LAMIDOL5: A pilot, open-label, single-arm (non-parallel), multicenter, 48 week trial primarily set in France. This study enrolled 110 patients who needed to have plasma HIV RNA less than 50 copies/mL for more than 2 years and CD4 count greater than 200/mm3. The study was designed so that participants would have an 8 week lead-in with triple therapy then switch to dual therapy. At Week 48, analysis was performed to see the proportion of participants who achieved therapeutic success (HIV RNA less than 50 copies/mL). At Week 48 the study results showed 101/104 (97%) participants had achieved therapeutic success.

ACTG A53536: A phase 2, single-arm, open-label study in United States that enrolled 120 ART naïve participants to be assessed at Week 52. The study required participants to have viral loads (VL) between 1,000-500,000 copies/mL and there were no restrictions in regards to CD4+ cells. The study’s primary end-point was to assess virological success (<50copies/mL) at Week 24 with safety and tolerability being secondary. At Week 24, 108/120 (90%) achieved virological success. As part of the secondary results, 10/120 (8.3%) experienced adverse effect although no participants discontinued the study due to adverse effects. This study was the first one to provide unique information about the feasibility of viral suppression. Additionally, DTG/3TC was efficacious at suppressing virus despite large zenith viral loads and it was the first study that showed the development of viral resistance (M184V, 106I, 263K).

GEMINI I1 and GEMINI II2: Two, nearly identical large phase III, randomized, double-blinded, multinational, multicenter, parallel studies that enrolled 719 and 722 ART naïve participants. The primary purposes of these studies were to assess the percentage of subjects with viral loads between 1,000-100,000 copies/mL and CD4>200/mm3 who achieved viral suppression (HIV VL<50 copies/mL) at Week 48. Preliminary results for these trials are expected to be released in the summer of 2018 and study completion is scheduled for March 2020.

In conclusion, dual ART comprising of DTG/3TC is a potent, safe, and to some extent cost-effective therapy when compared to conventional triple ART therapy.  Based on the current data available, dual therapy with DTG/3TC provides an intriguing option for those patients with exclusionary reasons to not use a regimen containing either abacavir or tenofovir and already exhibit a high level of medication adherence in either naïve or treatment experienced patients.  While the highlighted studies have shown optimistic results for ART naïve and experienced patients, results from trials with a larger sample size is needed.  Additionally, use of DTG/3TC in patients with archived drug resistance has yet to be explored.

References:

  1. An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 1). April 17, 2018. [NCT02831673]May 17, 2018
  2. An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir (DTG) Plus Lamivudine (3TC) With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 2). April 13, 2018, [NCT02831764] May 17, 2018
  3. Babafemi O Taiwo, Vincent C Marconi:Dolutegravir plus lamivudine maintains HIV-1 suppression through week 48 in a pilot randomized trial (ASPIRE), Clinical Infectious Diseases, Volume 66, Issue 11, 17 May 2018, Pages 1794–1797, [PubMed 29293895] May 17, 2018.
  4. Cahn P, Rolón MJ: Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE(Pilot Antiretroviral Design with Dolutegravir Lamivudine) study. Journal of AIDS international society. May 9, 2017, [PubMed 28537061] May 17, 2018.
  5. Taiwo BO, Zheng L: ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL. Clinical Infectious Diseases, Volume 66, Issue 11, 17 May 2018, Pages 1689–1697 [PubMed 29253097] May 17, 2018.
  6. Veronique Joly, Charles Burdet: A Trial Evaluating Maintenance Therapy With Lamivudine (Epivir®) and Dolutegravir (Tivicay®) in Human Immunodeficiency Virus 1 (HIV-1) Infected Patients Virologically Suppressed With Triple Highly Active Antiretroviral Therapy (HAART) (ANRS 167 Lamidol), French National Institute for Health and Medical Research-French, August 22,2017, [NTC 02527096] May 17, 2018.

Content provided by Freddy Orellana, UNMC PharmD Candidate ’18, and Joshua Havens PharmD

Men’s Health Month at UNMC ID

June is Men’s Health Month, a time to highlight the unique men’s health issues and advocate for awareness of preventive services for men and boys.  We have some amazing men in our division who have served as clinicians, educators, leaders, and mentors.

Meet the Men of UNMC ID:

Dr. M. Salman Ashraf, MBBS is an Associate Professor of Medicine and Medical Director of the Nebraska Infection Control Assessment and Promotion Program (ICAP). He also Co-Directs the Nebraska Antimicrobial Stewardship Assessment and Promotion (ASAP) Program with Dr. Trevor Van Schooneveld, and is Associate Medical Director Infection Control and Epidemiology at Nebraska Medicine. Dr. Ashraf’s clinical and research interests in antimicrobial stewardship and infection control in long-term care facilities (LCTF) have led to countless national speaker invitations and significant research funding granted to study antimicrobial stewardship and infection control in LCTF.

Dr. Scott Bergman, PharmD is an Infectious Diseases Trained Pharmacist, Clinical Associate Professor in the College of Pharmacy and Pharmacy Coordinator for the Nebraska Medicine Antimicrobial Stewardship Program. He also serves as the co Pharmacy Coordinator for the Nebraska ASAP program and has a special interest in appropriate antibiotic use and rapid diagnostic testing as an adjunct to antimicrobial stewardship. In 2016 and 2017 he was recognized as a Fellow in the Infectious Diseases Society of America (FIDSA) and American College of Clinical Pharmacy (FCCP), respectively. He works closely with our Infectious Diseases fellows and gives regular “antibiotic basics” lectures to the fellows and Internal Medicine residents.

Dr. Bradley Britigan, MD is the Dean of the University of Nebraska Medical Center College of Medicine, and Department of Internal Medicine Stokes-Shackleford Professor.  Despite his busy administrative duties, Dr. Britigan still finds time to practice clinically at the VA hospital, attends on our General ID teaching service, and contributes to our Division research meetings. His research interests include the pathogenesis of Pseudomonas spp. and Mycobacteria spp.  Lung Infections, and Microbial Iron Metabolism as a target for Novel Antimicrobial Therapies.

Dr. Paul Fey, PhD is a Professor in the Department of Pathology and Microbiology, Medical Director of the Clinical Microbiology Laboratory and Research Vice Chair of the Department of Pathology and Microbiology.  Our Division collaborates closely with Dr. Fey and the microbiology lab on implementation and improvement of diagnostic testing to improve clinical care. His research interests include the Metabolism and Pathogenesis of staphylococcal infections.  Just recently, Dr. Fey was honored with the 2017-2018 Outstanding Graduate Student Educator award in the department of Pathology & Microbiology at UNMC.

Dr. Josh Havens, PharmD is an Infectious Diseases-Trained Pharmacist with primary focus in the Specialty Care Clinic (SCC) which serves persons living with HIV (PLWH) in our Omaha and neighboring communities. He is leads the management team for the Ryan Wite AIDS Drug Assistance Program (ADAP) for the state of Nebraska. In his clinical role at the SCC, Dr. Havens not only facilitates discussions with clinicians and PLWH about complex medication issues, but runs a clinic for HIV pre-exposure prophylaxis (PrEP). This has fueled his primary research focus on the prevention of HIV as well as developing novel adherence strategies to keep PLWH healthy. He collaborates in these projects with Drs. Sara Bares and Susan Swindells.

Dr. Andre Kalil, MD is a Professor of Internal Medicine, and Director of the Transplant Infectious Diseases practice group at UNMC ID. He also holds board certification in Critical Care Medicine and has a special interest in infections occurring in the intensive care unit. Dr. Kalil is nationally and internationally recognized for his work in the field of severe sepsis, hospital acquired and ventilator acquired pneumonia, and was the first author and writing group leader of the recent IDSA/American Thoracic Society Guidelines on Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia. Dr. Kalil has acquired numerous grants with funding to study cytomegalovirus and other infections associated with solid organ transplantation.

Dr. James Lawler, MD, MPH is an Associate Professor of Medicine and Fellow in the Infectious Diseases Society of America (FIDSA). He is the Director of International Programs and Innovation, at the Global Center for Health Security and has led several teams to countries in West Africa focusing on Public Health Emergency Preparedness. Dr. Lawler, a former White House Homeland Security Council biodefense policy director, has national expertise on Biosecurity and viral hemorrhagic fevers, and is the current Director of Clinical and Biodefense Research at the National Strategic Research Institute.

Dr. Mark Rupp, MD our fearless leader is a Professor of Medicine and Chief of the Division of Infectious Diseases. He is a Fellow in the Infectious Diseases Society of America (FIDSA), Society for Healthcare Epidemiology of America (FSHEA), American College of Physicians (FACP) and past president of SHEA. He is also Medical Director of Infection Control & Epidemiology at Nebraska Medicine and Associate Director of Nebraska ASAP and ICAP. Dr. Rupp is also Chief of Medical Staff at Nebraska Medicine and has received the Top Teacher award in the Department of Medicine for almost a decade. He has published over 400 peer-reviewed articles and is nationally and internationally known for his expertise in healthcare associated infections, antimicrobial stewardship and staphylococcal infections.

Dr. Uriel Sandkovsky, MD is an Associate Professor of Medicine and Medical Director of Employee Health at UNMC. He attends on the Transplant Infectious Diseases service. His research interests include cardiac device infections and viral infections in transplantation.

Dr. Trevor Van Schooneveld, MD is an Associate Professor of Medicine and UNMC Infectious Diseases Fellowship Director. He is also Medical Director of our nationally recognized Nebraska Medicine Antimicrobial Stewardship program and Co-Director of the Nebraska ASAP with Dr. Ashraf. Dr. Van Schooneveld is a Fellow in the American College of Physicians (FACP) and actively involved in SHEA as an Associate Editor of the society flagship journal, Infection Control & Hospital Epidemiology (ICHE). Dr. Van Schooneveld’s areas of interest within the field of Antimicrobial Stewardship include reduction of C. difficile infections and use of infection biomarkers in clinical practice.

UNMC ID is looking for our next fantastic fellows! Could that be you?

Fellowship application season is nearing and as the Program Director for our ID fellowship, I wanted to highlight a few of the great things about our program.  Our fellows have a robust clinical experience that includes not only the typically complex patients seen at a tertiary referral center, but also includes extensive experience caring for immunosuppressed patients.  In addition to our General ID service, we have two separate immunocompromised services that care for oncology and solid organ transplant patients.  New this year we are adding an orthopedic infectious diseases rotation where fellows will gain dedicated experience managing these complex patients.  The faculty at UNMC are nationally recognized experts in their field, but are also very approachable and devoted to the education and success of trainees.  In addition to our inpatient experiences, fellows gain knowledge in HIV/AIDS management working in our multidisciplinary HIV clinic which cares for over 1200 persons with HIV.

An important part of fellowship is developing skills in interpreting and performing research and we provide our fellows with a 6 month mentored research experience centered on their career goals.  A research committee assists fellows in mentor identification and project development.  Fellows also participate in a two-week research training program provided by UNMC.  Fellows have the opportunity to be mentored by well-known experts in a variety of areas including HIV/AIDS, immunocompromised hosts, orthopedic infections, hospital epidemiology, antimicrobial stewardship, critical care infectious diseases, and biopreparedness.

As new career opportunities develop for ID physicians we have worked to provide our fellows with the skills to engage in these fields.  UNMC ID fellows receive extensive experience in the area of infection control and antimicrobial stewardship.  UNMC also offers the opportunity to stay for an option third year to further develop a research portfolio or to add a critical care medicine fellowship.  My goal as a program director is to provide fellows with an educational experience that provides them with skills and knowledge to make them successful in whatever career path they choose.  The opportunities available to ID physicians continue to expand and I hope you will consider UNMC ID.  If you are interested in more information, please feel free to visit our website and/or contact me.

Dr. Trevor Van Schooneveld

Program Director, Infectious Diseases Fellowship

Medical Director, Antimicrobial Stewardship Program
University of Nebraska Medical Center
985400 Nebraska Medical Center
Omaha, NE 68198-9400
Email: tvanscho@unmc.edu 


 

Interested in upcoming Transplant ID conferences? UNMC ID will be representing!

We are proud of our Transplant ID faculty who have demonstrated their academic productivity with invitations to present posters, oral lectures and moderate at upcoming Transplant ID conferences. If you are planning on attending any of these conferences, check out our faculty and staff presentations and tag us on twitter @UNMC_ID!

2018 American Transplant congress, Seattle, WA 2-6 June 2018

Dr. Andre C Kalil – moderator for “Frontiers in Cytomegalovirus – Bench to Bedside” Sunday June 3rd

Chambers HC, Kalil AC, Florescu DF. Timing of infections after TAH implantation. What did we learn? Jun 2-6, 2018 ATC, Seattle, WA. Poster

Florescu DF, Grimley M, Papanicolaou G, Prasad V, Vainorius E, Chittick G, Brundage T, Nichols T. Brincidofovir was Used to Successfully Treat Adenovirus Infections in Solid Organ Transplant Recipients and Other Immunocompromised Patients.. Abstract 294. Oral presentation. Jun 2-6, 2018 ATC, Seattle, WA

Henry M; Vacha M; Florescu DF; Keck M; Evaluation of the Use of Oral Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infections in Pediatric Intestinal Transplant Recipients: A Single Center Experience. Jun 2-6, 2018 ATC, Seattle, WA Poster

27th International Congress of the Transplantation Society, Madrid, Spain, June 30- July 5, 2018

Dr. Diana F Florescu – oral presentation: Addressing the Threat of Infections Post-Transplant – Diarrhea in Transplantation, July 1, 2018

Dr. Diana F Florescu – oral presentation: Early Morning Symposium – Challenging Cases in Transplant Infectious Diseases: Pushing the Boundaries of Donor and Recipient Outcomes – Polyoma Viruses. July 4, 2018

Chambers HC, Kalil AC, Florescu DF. Hospital Course after TAH Implantation, Nebraska Experience. Poster session 2, P.398. TTS 2018, Madrid Spain


 

Pseudomonas In Cystic Fibrosis lung disease: Time to dispense with the shotgun approach

WE are absolutely THRILLED to have Dr. Dickinson write this guest blog post in honor of Cystic Fibrosis Awareness month. There are few conditions in which antimicrobial treatment is determined at least in part, by organ function, and CF is one of those states. Here at UNMC ID, we are committed to bringing colleagues together to teach each other, garner greater understanding and hopefully foster further collaboration. This wonderful commentary by Dr. Dickinson teaches us about Cystic Fibrosis, Treatment of infections, new studies on the horizon and supports the stewardship dogma of targeted therapy!

Management of Pseudomonas aeruginosa airway infection in cystic fibrosis lung disease: Time to dispense with the shotgun approach in favor of a targeted approach with precision therapeutics.

By Dr. John Dickinson, MD, PhD

Associate Director Adult Cystic Fibrosis Center UNMC

Assistant Professor of Medicine

Division of Pulmonary, Critical Care, Sleep, & Allergy

 

Cystic Fibrosis (CF) is an autosomal recessive genetic disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) gene leading to abnormal chloride ion transport. Approximately 30,000 individuals in the United States have CF. There has been extraordinary improvement in the survival among those with CF and life expectancy has increased from the late adolescent years in the 1980s to the mid 40s today. There are now more adults living with CF than children (Figure 1). New CFTR modulators developed within the last 6 years offer further hope to CF patients to prevent bronchiectasis and loss of lung function.

In the airways, lack of chloride transport from dysfunctional CFTR leads to reduced airway surface liquid. As a consequence, normal mucociliary clearance is drastically reduced as airway mucus is thick and tenacious. This defect of innate immunity leads to a failure to clear pathogens from the airway. Early in life, children develop infections with Staph aureus, streptococcus pneumoniae, and hemophylus influenzae. Later in life, however, CF patients may be infected with Pseudomonas aeruginosa. Due to the fundamental defect in mucociliary clearance, the Pseudomonas infection develops mucoid strains with biofilm development in the airways. Most CF centers, including ours at UNMC, define chronic infection as presence of a microorganism in >50% of sputum cultures in the preceding 12 months. CF patients with chronic pseudomonas infection have reduced lung function and survival compared to non-infected persons.1,2,3 Therefore, CF clinicians aggressively treat chronic Pseudomonas infection of the airways and prevent CF pulmonary exacerbations which accelerate lung function decline.4

Given the fundamental mucociliary defect, the anti-pseudomonal strategy is palliative rather than curative- to reduce the microbial burden of disease. Antibiotics remain the workhorse for this strategy. As the airway concentration can be up to 100x higher with nebulization vs. systemic administration, inhaled antibiotics are the primary modality. In the 1990 several RCT indicated that nebulization of tobramycin in CF patients with Pseudomonas infection increased lung function, reduced pseudomonas sputum density, improved quality of life, and increased the time to next exacerbation (Figure 2).5,6 A number of formulations have been approved. The most common rely on 300mg dose of tobramycin nebulized for inhalation twice a day for 28 days. Early clinical trial design and subsequent practice patterns have patients alternate months off and on therapy. As with all aminoglycosides, nephrotoxicity and ototoxicity are potential adverse effects to monitor. Chronic administration of aerosolized antibiotics may alter antibiotic susceptibilities as well. The NEJM study noted a slight increase in the proportion of patients with tobramycin MIC> 8mg/ml at the conclusion of the study- although this was less than the effect from intravenous tobramycin.5

Patients with CF have a tremendous treatment burden that may add up to 1-2 hours per day on average7. Airway clearance, nebulized treatments, pancreatic enzyme replacement, insulin management for diabetes all require significant resources and time each day. Dry powder formulations of tobramycin have been introduced that improve compliance due to ease of use and reduced treatment time. The EAGER trial demonstrated that dry powder tobramycin has similar efficacy as nebulized tobramycin.8

In 2010, nebulized aztreonam was approved for patients with chronic Pseudomonas airway infection. As with tobramycin, treatment strategy is 28 days on and 28 days off therapy. TID dosing of nebulized aztreonam had similar efficacy as tobramycin when randomized to placebo9-10. Although strong clinical data is lacking, most CF clinicians alternate aztreonam and tobramycin to give patients continuous anti-pseudomonal treatment. The CAT trial attempted to address if using continuous alternating antibiotics (both aztreonam and tobramycin) was superior to single agent (tobramycin alone) with no second drug during the off month. Unfortunately, enrollment was limited as clinicians and patients were reluctant to change what had become standard practice- to treat with continuous inhaled antibiotics. Therefore, no firm conclusion could be determined11.

Azithromycin has pleotropic qualities involving the macrolide ring structure that reduce neutrophil mediated inflammation in CF. Several trials indicate that CF patients with chronic Pseudomonas airway infection have the greatest benefit from azithromycin.12,13 Standard regimen is 500 mg of azithromycin (250mg in children) on three days a week schedule -typically alternating days. According to CF Foundation registry data, the majority of those on inhaled tobramycin for chronic pseudomonas infection also were treated with azithromycin. Interestingly, recent post-hoc analysis of clinical trial data14 and in vitro data15 suggests that azithromycin may negatively interact with tobramycin by inducing antibiotic resistance factors in Pseudomonas strains. Analysis of clinical trial data from

the inhaled aztreonam study revealed that CF patients chronically treated with both inhaled tobramycin and oral azithromycin had no improvement in lung function compared to those co-treated with aztreonam and azithromycin (Figure 3). While this was a post-hoc analysis in a heavily pre-exposed tobramycin cohort, it does raise sufficient concern to warrant further study. In vitro, azithromycin treatment of clinical pseudomonas isolates led to antagonism of concurrent tobramycin treatment with a reduction in the antibiotic mediated-decrease in colony forming units (CFU) and increase in pseudomonal drug efflux pump genes, MexXY (Figure 3). This potential serious drug-drug interaction led to the launching of a new study, the TEACH trial that will prospectively evaluate the interaction between azithromycin and inhaled tobramycin. The lesson remains that no therapy is completely benign and drug interactions may have un-intended consequences. It is also for difficult for physicians to stop any chronic treatment that patients have been on for years when effectiveness is difficult to gauge.

On the horizon, new antibiotic and non-antibiotic strategies are emerging. Clinical trials are underway for nebulized liposomal amikacin and levofloxacin. IV Gallium is FDA approved for MRI contrast. Gallium has iron chelating properties that interfere with Pseudomonas iron metabolism leading to reduction of both planktonic and biofilm pseudomonas levels.16 The Adult CF Center has been part of the phase II clinical trials looking at IV Gallium in CF patients chronically infected with Pseudomonas.

The CF community has often taken a shotgun approach to management of a deadly disease that had, until recently, a life expectancy only into late adolescence or early adulthood. New therapies including new CFTR modulators that improve Cl- transport in the airways offer to change the paradigm of CF treatment. As we enter into this new era, CF clinicians will need to re-examine practice patterns of indefinite antibiotic treatment of chronic mucoid pseudomonal airway infection. New randomized controlled trials will be needed to explore the optimal treatment strategy. This strategy will likely involve both antibiotic and non-antibiotic anti-microbial agents to maximize outcomes in CF while reducing adverse effects.

 

 

References:

  1. Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, and Grimwood K. J Pediatrics. 2001 May;138(5):699-704.
  2. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pediatric Pulmonology. 2002 Aug;34(2):91-100.
  3. Henry RL, Mellis CM, Petrovic L. Pediatric Pulmonology. 1992 Mar;12(3):158-61.
  4. de Boer K. Vandermheen KL, Aaron SD, et al. Thorax 2011;66:680-685.
  5. Ramsey BW, Pepe MS, Smith AL, et al. NEJM. Jan 7th 1999; 340:23-30.
  6. Moss R. Chest. 2002; 121(1):55-63.
  7. Sawicki GS, Sellers DE, Robinson WM. Journal of Cystic Fibrosis. 2009 ; 8(2) : 910-96.
  8. Konstan MW, Flume PA, Geller DE, et al. Journal of Cystic Fibrosis. 2011 January; 10(1): 54–61.
  9. McCoy KS, Quittner AL, Montgomery AB, et al. Am J Respir Crit Care Med. 2008 Nov 1;178(9):921-8.
  10. Retsch-Bogart GZ, Quittner A, Cooper PJ, et al. Chest 2009;135(5):1223-1232.
  11. Flume, PA, Clancy JP, Ramsey BW, et al. Journal of Cystic Fibrosis. 2016;15(6):809-15.
  12. Saiman L, Marshall BC, Campbell, PW, et al. JAMA. 2003;290(13):1749-56.
  13. Saiman L, Marshall BC, Ratjen F, et al. JAMA. 2010 May 5;303(17):1707-15.
  14. Nick J, Moskowtiz SM, Nichols DP, et al. Annals of the American Thoracic Society. 2014; 11:(3): 342–350.
  15. Nichols DP, Happoldt CL, Nick JA, et al. Journal of Cystic Fibrosis. 2017;16:358-66.
  16. Kanenko Y, Britigan BE, Singh PK, et al. Journal of Clinical Investigation. 2007; 117(4):877-888.


 

Dogma vs. Necessity: Follow-up blood cultures in patients with gram-negative negative bacteremia

Attending on the inpatient Infectious Disease service always stimulates discussion regarding management of bloodstream infections: What is the optimal duration? Can we use oral antibiotics? Do we need to document clearance of blood cultures? When these discussions lead to review of literature, one will find that the data is evolving in an attempt to answer these questions. Last month’s ID journal club included spirited discussions about one of these questions, led by our ID Division Chief, Dr. Mark Rupp.

Dr. Rupp reviewed an article by Canzoneri CN, et al:  Follow-up blood cultures in gram-negative bacteremia: are they needed? Clinical Infectious Diseases. 2017;65(11):1776-9.

It is well accepted that patients with Staphylococcus aureus bloodstream infection (BSI) require follow-up blood cultures at day 2-4 to establish whether the infection should be classified as complicated, thus requiring at least 4 weeks of antibiotics. Unfortunately, many clinicians extrapolate from experience with S. aureus BSI and apply the same practice to patients with BSI due to gram-negative bacilli. There is little data to support routine follow-up blood cultures in patients with gram-negative bacilli BSI. Therefore, Canzoneri and colleagues at the University of Texas Health Science Center in Houston reviewed their experience in 500 patients with bloodstream infection during the year 2015.

Of 500 patients with bloodstream infection, 383 (77%) had follow-up blood cultures. Of the 383 patients with follow-up blood cultures, 140 had a bloodstream infection due to gram-negative bacilli and only 8 (5.7%) follow-up blood cultures were positive. In contrast, 43 patients (20.8%) of patients with gram-positive cocci BSI had positive follow-up blood cultures. The only factor that predicted a positive follow-up blood culture in patients experiencing bloodstream infection due to gram-negative bacilli was fever at the time of the follow-up blood cultures. Other risk factors examined included whether the patient was receiving antibiotics, the presence of a central venous catheter or urinary catheter, neutropenia, HIV, diabetes, end-stage renal disease on hemodialysis, cirrhosis, ICU care, and mortality. Thus, 17 follow-up blood cultures had to be obtained in patients with gram-negative bacilli BSI in order to define one person with persistent bacteremia.

The authors concluded that routine follow-up blood cultures in patients with gram-negative bacilli bloodstream infection has little value and probably results in added costs and inappropriate use of antibiotics.

For those interested in the topic, another recent study showing that repeat blood cultures are generally unnecessary in patients with gram-negative bacilli bacteremia is Wiggers JB, at al. BMC Infectious Diseases 16:286 (2016).

Along a similar thought line related to misuse of blood cultures – what data supports the common practice of starting the “antibiotic clock” when repeat blood cultures are sterile?  To the best of my knowledge, there is very little information to support this common clinical practice.  I think in most instances, even in S aureus BSI, this dogmatic practice results in prolonging antibiotic course duration by a few days with associated increases in cost, toxicity, and emergence of resistance with very little demonstrated benefit to the patient.

Content courtesy Dr. Mark Rupp MD.

DANCE FOR A CHANCE with UNMC ID’s Dr. Diana Florescu

There are hundreds of homeless youth in Omaha. Some of them have been emotionally, physically, or sexually abused, making it unsafe for them to return home, while others are facing health, mental health, or substance abuse issues. Youth Emergency Services (YES) provides much needed services for these individuals.

What is YES Dance for a Chance? Dance for a Chance is an event where local representatives from several companies compete to raise awareness and money for YES and the homeless youth of Omaha. This event and all of its proceeds are for the homeless youth of Omaha. At the end of the competition, there will be 3 winners – the team with the most votes (money), the team with the best dance, and most importantly, the homeless youth of Omaha. More information can be found here.

Dr. Diana Florescu, Associate Professor in the Division of Infectious Disease, is the UNMC representative in the 2018 Dance for a Chance competition. She is partnering with Derek Pasqualetto, instructor and owner of Vintage Ballroom.

In the following weeks, there will be updates and sneak peeks of the campaign. Your support is needed to help provide critical resources to homeless youth and to bring the trophy to UNMC. You will be able to follow us on Facebook.

Voting is open NOW! Click here to vote for Dr. Diana Florescu or make a donation to YES Omaha.

Please support and cheer on Dr. Diana Florescu and her partner at the Dance for a Chance event! The event will take place on Friday, August 3, 2018 at 6:00 p.m., at the Omaha Design Center, 1502 Cuming St Omaha, NE 68102. Get 10 friends together and purchase a table! If interested please contact Dr. Florescu at dflorescu@unmc.edu.

Thank you in advance for all the support!!!

Content provided by Ada Florescu

Interested in Orthopedic Infectious Diseases? The Perfect Job Awaits You at UNMC!

Orthopedic Infectious Diseases
University of Nebraska Medical Center – Omaha, NE

The University of Nebraska Medical Center (UNMC) is excited to announce the recruitment of a faculty position in Orthopedic-ID in the Division of Infectious Diseases, Department of Internal Medicine. Successful candidates will hold an academic appointment at the assistant or associate professor level and will be employed by UNMC and Nebraska Medicine. Candidates should be Board Eligible/Certified in Infectious Diseases.

A generous compensation package with salary commensurate with experience will be offered. Candidates should have an enthusiasm for patient care, teaching, and clinical research. Generous protected time and support are available in order to conduct collaborative clinical research and achieve the goals of the program.

Opportunity Highlights:
– Join established ID Physicians, two Advanced Practice Providers, an ID-trained Pharmacist, and dedicated pharmacy technician in a newly established Orthopedic ID Service Line and support the Outpatient Antimicrobial Therapy (OPAT) Program
– Partner with an internationally-recognized Antimicrobial Stewardship Team to develop and implement OPAT at Nebraska Medicine
– Participate in teaching of medical students, residents, and ID fellows on the Ortho ID consult service

The successful applicant will also participate in the clinical, teaching, and research programs of the Infectious Diseases Division – a vibrant and growing division made up of 18 ID faculty.

Translational research between the Ortho ID program and the Center for Staphylococcal Research is encouraged.

Learn more about UNMC ID on our website and the UNMC ID blog. You can also follow our Division on Twitter @UNMC_ID.

Interested candidates should submit a letter of interest and CV to:

Mark Rupp, MD
Chief, Division of Infectious Diseases
University of Nebraska Medical Center
985400 Nebraska Medical Center
Omaha, NE 68198-9400
Email: merupp@unmc.edu

UNMC ID Division Accolades!

Our Faculty at University of Nebraska Medical Center Division of Infectious Diseases have worked hard to maintain a strong academic presence at UNMC. We are a growing division, filled with faculty at all stages of their careers, and their collective academic prowess has our division leading the pack. Our recent Department of Medicine Research report for 2017 pegged UNMCID as the #1 Division for the number and amount of extramural contracts/awards and #2 for number of publications (out of 10 Divisions in Internal Medicine). We recently had several posters and oral presentations presented at #CROI2018, #SHEA2018 and #ECCMID2018. We are proud of our faculty and would like to share some of their accomplishments with our followers.

Dr. Alison Freifeld has been invited to speak at #IDWeek2018 on new developments in the management of cancer patients, and she is on the steering committee for the American Council on Education (ACE) program at UNMC: goal is to internationalize our campus/curriculum/student body.  This program is mandated by the Chancellor and reflects UNMC’s commitment to expanding our efforts in international engagement and global health education and research.

Dr. Jasmine Marcelin was recently co-recipient of the award for Outstanding multi-site Quality Improvement Project for 2017 – Mayo Clinic Quality Review Board {Project: Management of Febrile Neutropenia (MOFN), completed as a fellow with Drs. Jack O’Horo and Omar Abu Saleh}. Dr. Marcelin also co-authored recently published papers about  Mycobacterium genavense infections in non-HIV immunocompromised hosts (Infectious Diseases) and Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923–2016 (Clinical Infectious Diseases).

Dr. Susan Swindells was recently highlighted in ground-breaking research likely to change the paradigm of latent TB treatment in persons living with HIV; presented at #CROI2018: One Month of Rifapentine/Isoniazid to Prevent TB in People with HIV.   Dr. Swindells also collaborated with UNMC colleagues (including Jennifer O’Neill, RN of the Specialty Care Clinic) on a recent paper published in Brain: Aberrant occipital dynamics differentiate HIV-infected patients with and without cognitive impairment.

Dr. James Lawler  (former White House Homeland Security Council biodefense policy director) was recently called upon to share his expertise pertaining to Biosecurity at the Blue Ribbon Study Panel on Biodefense, where he cautioned that we are unprepared for biological threats that may affect our country and the world.  He called for a new paradigm of innovation to prepare ourselves for future threats. A video of his testimony can be found here.

What a terrific group of talented and accomplished individuals.  Kudos to our faculty and staff for their continued hard work and dedication to advancing academic Infectious Diseases!

EMET Student Profile – Kevin Hanna, M1

Tell us about the position you are starting? I am a first-year medical student who is beginning the four year Enhanced Medical Education Track (EMET) program with a focus in HIV medicine. The program includes opportunities for preceptorships, seminars, volunteering, and research in HIV medicine culminating in a capstone research project and poster or conference presentation.

Background: I grew up in Bellevue, Nebraska and graduated from Bellevue West High School. I completed my undergraduate education at the University of Nebraska-Lincoln, with a Bachelor of Science degree in Microbiology. When I’m not studying, I love to read and run long distance races.

Why UNMC? Being a Nebraska native, I have always been interested in UNMC as an avenue to be at the center of patient care in Nebraska. When I was in high school, I participated in one of the inaugural classes of the UNMC High School Alliance, where I took Anatomy, Public Health, and Clinical Microbiology courses that piqued my interest in medicine and population health. These experiences drove me to pursue an undergraduate degree in Microbiology. This program helped me fall in love with the university, and I always hoped I would be able to come back for medical school. Additionally, I was very driven to the unique academic and clinical opportunities Nebraska Medicine provides, and am excited to be a part of the premier health system in the region.

What about ID and HIV medicine makes you excited?  I am drawn to the inherent detective work involved with Infectious Disease, and it makes me excited to use aspects of many different disciplines to solve complex, multi-system disease processes. My experiences in my undergraduate education have developed a passion for understanding the biological processes that drive diseases caused by microbial pathogens, and I am interested in tailoring treatment regimens to fight diseases caused by specific pathogens. I am especially excited to participate in this EMET, because I think HIV medicine combines infectious disease, population health, social determinants of health, and pharmacological breakthroughs in very exciting ways. I am excited to not only learn more about what it means to be an infectious disease physician, but also learn how to be a better physician through nuanced and rewarding patient interactions.

We wish Kevin the best of luck over the next several years during his journey with us as part of the HIV EMET! More information about the EMET program can be found here.

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