Download Infectious Diseases - USC Internal Medicine Residency Program

Keck School of Medicine of USC
Faculty
Professor
Professor Emeritus
Assistant Professor
Michael P. Dubé, MD (Clinical Scholar)
Paul D. Holtom, MD
Fred R. Sattler, MD
Brad Spellberg, MD
Robert A. Larsen, MD
Emily Blodget, MD
Joseph J. Cadden, MD
Darren W. Wong, MD
Associate Professor
P. Jan Geiseler, MD
Brenda E. Jones, MD
66
Department of Medicine 2015
Infectious Diseases
Fred R. Sattler, MD, Professor of Medicine and Chief
Erika Anaya, Division Administrator
The overarching mission of the Division of Infectious Diseases is threefold: to advance the development of therapies
to improve health through clinical and translational research in infectious diseases; to promote excellence in the
education of medical students, house officers and clinical fellows; and to deliver compassionate, evidence-based,
state-of-the-art care to the large, diverse, multicultural community of Southern California served by LAC+USC
Medical Center (LAC+USC), Rand Schrader Health and Research Center, Keck Hospital of USC, USC Norris
Cancer Hospital (Norris Hospital), and the USC Healthcare Center 2 (HC2).
A primary research mission of the Division of Infectious Diseases for more than three decades has been to
investigate strategies to prevent and treat HIV and its complications. The NIH-supported AIDS Clinical Trials
Group (ACTG) is a major focus of research in the Division. Dr. Fred Sattler serves as Principal Investigator. The
ACTG Clinical Research Site (CRS) at USC is in its 28th year and recently successfully re-competed to be funded
for another seven-year cycle. The USC ACTG CRS has continuously performed at a very high level and has been
second in enrollment of total research subjects amongst 72 domestic and international sites. It is also the leading
site in the continental U.S. for enrolling minorities and women. Moreover, USC faculty (Drs. Sattler and Dubé,)
continue to hold important scientific and administrative leadership positions during the current funding cycle. These
key positions enabled faculty from our Division to contribute to and facilitate the scientific agenda and productivity
of this world-leading HIV collaborative research group. Tuberculosis, hepatitis C and cryptococcal meningitis, along
with complications of chronic inflammation and immune activation including cardiovascular and lipid disorders
and neurocognitive impairment, and aging-related disabilities including frailty have been areas of leadership by ID
faculty. Drs. Dubé and Sattler are members of the Inflammation and End-Organ Transformative Science Group and
have developed a number of concept proposals that are either under review or are being implemented for studies.
Dr. Sattler is Chair of the Exercise Focus Group and Dr. Dubé is a member of the Data Monitoring Committee.
The Division of Infectious Diseases also remains a lead member of the California Collaborative Treatment
Group (CCTG), which is funded by the State of California University Wide AIDS Program. The CCTG is the
largest collaborative HIV clinical research group in California and has been continuously funded for more than
two and a half decades. Dr. Dubé is the Principal Investigator of the USC component of the CCTG. Under his
leadership, the CCTG was recently awarded $1.6 million to lead a large four-year CCTG project at USC and
the other collaborative research sites to improve patient retention in HIV care and to provide HIV pre-exposure
prophylaxis (PrEP) to individuals at high risk of acquiring HIV.
The Rand Schrader Health and Research Center has been under the medical leadership of the Division
(Drs. Sattler, Cadden and Dubé) since 1986 and has been a national flagship for the outpatient care of persons with
HIV. The Clinic was conceived around a model whereby all care would be facilitated at a single site, the “medical
care home.” Up to 40 USC faculty from virtually all specialties provide primary care and consultation during 11
weekly clinics session (Monday through Friday AM and PM as well as Tuesday evenings for patients who work
during the daytime). A primary care provider, a registered nurse and a social service case manager constitute the
Medical Care Coordination team for each patient; they facilitate all aspects of patient care in and away from the
Clinic (including in the patient’s home).
Specialty clinics have included Pulmonary, Hematology-Oncology, Neurology, Psychiatry, Ophthalmology,
Colorectal and Nutrition-Metabolism. Two new clinics have been created to meet the changing face of chronic HIV
infection. The Dermatology service staffs a weekly Lipodystrophy Clinic, whereby patients receive autologous fat
67
Keck School of Medicine of USC
transfer for facial wasting, or liposuction to relieve pain and suffering associated with buffalo humps or other fatty
depositions. The other new clinic is the Hepatitis Treatment Evaluation Clinic for patients co-infected with HIV and
HCV or HBV. The goal of this clinic is to treat all patients co-infected with HBV and HCV at increased risk for
liver related complications, especially now as multiple oral agents are available.
The Rand Schrader Health and Research Clinic also sponsors a broad range of education programs in HIV for
the faculty, staff, ID fellows and other house officers rotating through the adult and pediatric ID services. As
just one example, a Resistance Workshop is held monthly where patients with complex HIV resistance profiles
and multiclass drug-resistance profiles are presented. Attendees use cART treatment histories along with HIV
phenotypes and genotypes and work with an expert facilitator to arrive at treatment recommendations. The Clinic
also serves as the primary site for OPD continuity care for ID fellows who learn all aspects of ambulatory care of
HIV.
The Infectious Diseases Solid Organ Transplant Consultation Service was created in the spring of 2010 to
provide complex ID consultation for a large number of solid organ transplants (heart-lung, liver, pancreas and
kidney) at Keck Hospital. Dr. Emily Blodget serves as the lead consultant with assistance from Drs. Cadden,
Geiseler and Sattler in creating the first dedicated infectious diseases transplant service at Keck Hospital. This
addition provides a unique and focused training experience for infectious diseases fellows, house officers and
students rotating through the ID consultation service.
The unique tripartite training in Infectious Diseases at USC offers an unparalleled clinical experience in three
very different settings. First, the new training experience in transplantation infectious diseases is complemented by
existing training provided by highly experienced faculty on the inpatient general ID consultation services at two
private university hospitals (Keck Hospital and Norris Hospital), serving privately insured patients. The second
involves the very busy ID consultation service at LAC+USC, which provides care to the underserved population
of the greater Los Angeles Basin, many of whom are recent immigrants and travelers who bring from their home
countries infections not routinely seen in the United States. The third component involves unparalleled opportunities
for training in HIV medicine at the 33,000-square-foot, fully dedicated Rand Schrader Health and Research Clinic,
which provides primary and specialty HIV care for approximately 2,500 HIV infected individuals. LAC+USC and
the Rand Schrader Clinic provide care for a largely underserved minority population (60-70% Latinos and 12-15%
African-Americans). The clinical and racial/ethnic diversity make ID fellowship training at USC one of the truly
unique programs in the U.S.
Dr. Brad Spellberg, previously a faculty member at Harbor UCLA, was recruited to USC last year to serve as
Chief Medical Officer for LAC+USC Medical Center. He is also an active member of the Division of Infectious
Diseases, attends regularly on the ID consult services and participates in all other teaching functions in the Division
(including weekly cases conferences, ID grand rounds and CPCs, journal club, and research seminars—see below).
Dr. Paul Holtom now serves as Director of Infection Control and and Prevention at LAC+USC Medical Center
and is the founder and leader of the Orthopedic ID service at the facility; Dr. Holtom like Dr. Spellberg attends and
participates in all of the teaching activities of the ID Division.
Dr. Darren Wong joined the Division of Infectious Disease in July after completing
his ID fellowship training at Montefiore Medical Center and Albert Einstein College
of Medicine. Dr. Wong has assumed leadership and lead roles in the antimicrobial
stewardship programs at LAC+USC Medical Center and Keck Hospital, monitoring all
daily blood cultures as done by the ID fellows, and for the large weekly communicable
diseases clinic at Rand Schrader Clinic. He also serves in a support capacity to
Dr. Paul Holtom, Infection Prevention Officer, at the LAC+USC Medical Center.
Dr. Wong serves on the ID consultation services at Keck Hospital and LAC+USC
Medical Center. For his research, he works with Dr. Brad Spellberg on studies of
antimicrobial resistance and therapeutic strategies for these infections (including
monoclonal antibody and vaccine development).
The Division of Infectious Diseases provides care and consultation in all the clinical venues served by the
Department of Medicine at the University of Southern California.
68
Department of Medicine 2015
LAC+USC Medical Center/Outpatient Clinics
Rand Schrader Health and Research Clinic
The ID Division maintains overall responsibility for the medical operations of the Rand Schrader Clinic. Dr. Cadden
serves as Medical Director and Dr. Dubé as Associate Medical Director. This modern facility is fully dedicated to
the comprehensive care of persons infected with HIV. Faculty from the Division and all other major specialties
provide primary and specialty care and serve as attending physicians for house officers and students. Patients
receive primary care at the Clinic mornings and afternoons Monday through Friday and Tuesday evenings.
Hospital Infection Control and Antibiotic Stewardship
Dr. Paul Holtom serves as the Hospital Epidemiologist, Infection Control Officer and heads Infection Prevention at
LAC+USC. He also oversees the Antibiotic Stewardship Program (ASP), as well as chairing the Infection Control
Committee, the Pharmacy and Therapeutics Committee and the Antibiotic Subcommittee at LAC+USC Medical
Center. Drs. Sattler and Dubé also serve on the Antibiotic Subcommittee. Drs. Wong and Dubé are members of the
ASP and make daily teaching and stewardship rounds with pharmacists at LAC+USC, with special focus on critical
care and hematology units and services.
Keck Medical Center of USC
Drs. Geiseler, Cadden, Blodget, Wong and Sattler provide consultative inpatient services (both teaching and private)
and outpatient services at Keck Hospital and HC2, respectively there are more than 2,000 new patient consultations
annually at this facility. Dr. Blodget also serves as the Interim Hospital Epidemiologist. Dr. Sattler oversees the
Antibiotic Stewardship Program at this facility and makes daily antimicrobial stewardship rounds with a hospital
pharmacist and Drs. Blodget, Cadden and Geiseler to evaluate patients receiving restricted antibiotics and to help
the primary care teams in the management of their patients. Dr. Dubé serves as compliance officer for the USC
Clinical Trials Unit at Norris Hospital.
USC Healthcare Centers
Drs. Cadden, Geiseler, Blodget and Wong have regularly scheduled weekly outpatient clinic sessions for ID patients
at these facilities. The clinics generate approximately 1000 outpatient visits annually. These faculty also provide
consultations for outgoing international travelers needing prophylaxis and immunizations and for returning travelers
with new signs and symptoms of infections acquired overseas. They also oversee outpatient IV antimicrobial
therapy for patients recently discharged for Keck and Norris hospitals.
69
Clinical Activities
The Division provides a very active consultation service (approximately 3,000 new infectious diseases consultations
each year) at LAC+USC. The Division also operates a weekly general ID outpatient clinic (~1,000 visits annually),
staffed by ID faculty (Drs. Dubé, Sattah, Jones and Wong), fellows, residents and students who provide outpatient
consultation and continuity care for patients with and without HIV who have complicated infections or those
needing outpatient IV antimicrobial therapy.
Keck School of Medicine of USC
Educational Activities
Infectious Disease Fellows
Class of 2016
Class of 2017
Supriya Bhat, MD
Daniel Chelliah, MD
Melissa Barger, MD
Rohit Kaliah, MD
Elham Rahmati, MD
The Infectious Disease Fellowship program has grown from four to five trainees and will have a sixth fellow trainee
in July 2016. The addition of trainees provides greater diversity in electives (e.g. stewardship, clinical microbiology,
infection control/prevention, ortho ID) with greater flexibility for research projects.
Conferences
The Infectious Diseases Core Lectures (Monday mornings 8:00-9:00) are a vital component of the
didactic portion of the ID curriculum and provide a comprehensive overview of virtually all important infectious
diseases topics over a two-year cycle. Lectures are usually given by ID faculty, but each fellow is expected to give
one to two lectures annually.
The Infectious Diseases Case Conference (Wednesday mornings 8:30-9:30) features two case
presentations, usually one from the LAC+USC Consult Service and one from the Keck or Norris Hospitals; one
case per month is selected from the Pediatric ID Service. Fellows unfamiliar with the cases discuss diagnostic
and therapeutic issues. Faculty then provide additional insights into the case, followed by a five minute didactic
presentation by one of the fellows that highlights important or unique aspects of the cases presented. This lively
conference is usually attended by 30-40 participants, including faculty, trainees, Rand Schrader Clinic providers and
community ID practitioners.
Infectious Diseases Grand Rounds (second Friday of each month) features guest speakers selected and
hosted by the USC ID faculty, including visiting faculty of local and national stature in their respective areas of
expertise.
70
Department of Medicine 2015
The Clinicopathologic Conference (fourth Friday of each month) is a multidisciplinary conference that
includes faculty from other specialties who discuss diagnostic elements and review pathologic slides, microbiologic
specimens, radiographic imaging, retinal photographs and/or their specialty’s contribution to the patient care of the
case presented.
For Infectious Diseases Journal Club (monthly), two articles are selected by an ID faculty facilitator.
One fellow is assigned as the primary presenter/discussant for each article, presenting a critical analysis of
study hypotheses, study design, statistical methods, results and appropriateness of the authors’ conclusions, and
applicability of the results to patient care.
The Combined Pulmonary-Infectious Diseases Teaching Conference (third Tuesday morning
8:30-9:30) consists of case presentations of two unknowns, one selected by ID and the other by Pulmonary. Faculty,
fellows, residents and students from both divisions attend the conference and participate in the discussion of
instructive cases. A short review of the relevant literature follows each presentation.
Intercity Infectious Diseases Rounds is a long-standing two-hour monthly meeting of academic ID
specialists, trainees and allied health professionals that rotates among the participant hospitals (USC, Harbor UCLA,
Harbor City Kaiser, St. Mary’s Medical Center, Long Beach VA and Torrance Memorial Hospital). Four to five cases
are presented as unknowns and discussed by faculty selected at the conference by the facilitator from the hosting
institution. At the end of each case presentation, a fellow from the sponsoring facility gives a didactic slide overview
of salient features of the case.
Combined Adult-Pediatric Infectious Diseases Research Conference is a monthly clinical
research conference (coordinated by Dr. Dubé) on topics of current clinical and translational research of adult and
pediatric ID faculty, other USC faculty (e.g. from the School of Pharmacy, Department of Molecular Microbiology
and Immunology), and clinical fellows of USC and, CHLA; occasionally guest experts from affiliated institutions
(e.g., City of Hope) give seminars. The conference is interactive and participants discuss study design, statistical
approaches and analytical methods.
Faculty Research Areas
Emily Blodget, MD
Dr. Blodget has initiated research on the incidence and outcomes of vancomycinresistant enterococcus (VRE) infection in patients with cirrhosis who are awaiting
liver transplantation. She is conducting a large ongoing retrospective study in these
patients to determine the risk factors as well as morbidity and mortality of VRE
infection. She is planning on expanding these studies to include other multi-drug
resistant organisms such as pseudomonas and ESBL E. coli. She is continuing to
develop research plans to evaluate the effectiveness of screening liver transplant
candidates with interferon gamma release assay versus standard PPD testing and
outcomes after transplant.
71
Research Activities
The Division maintains consistent funding for ongoing investigations relating to HIV and other areas of infectious
diseases. The Division has had an important and productive role in large, multicenter collaborative research groups
that emphasize development of treatment and prevention modalities for HIV infection and complications associated
with antiretroviral therapy and the underlying disease as well as other bacterial, fungal, and viral infections in HIVpatient populations.
Keck School of Medicine of USC
Joseph J. Cadden, MD
Dr. Cadden is conducting several important studies. He serves as Co-PI with Amy Wohl, PhD (Chief Epidemiologist
in the HIV Epidemiology Program, Los Angeles County Department of Health Services), on an NIH-funded
investigation to evaluate and develop better social support services for persons with HIV. He is also a member of
the protocol team for ACTG 5293, which evaluates the effect of HDL-raising therapies on endothelial function,
lipoproteins and inflammation in HIV-infected subjects with low HDL cholesterol.
Michael P. Dubé, MD
Dr. Dubé’s research interests focus on the complications of HIV infection as well as on HIV prevention. He has
been the USC PI of the California Collaborative Treatment Group (CCTG) for HIV research since 2009; the CCTG
is the largest collaborative HIV clinical research group in California and is funded by the California HIV Research
Program. Currently, Dr. Dubé is wrapping up a major 4-year CCTG project at USC to improve patient retention
in HIV care and to optimize HIV pre-exposure prophylaxis (PrEP) to individuals at high risk of acquiring HIV.
As part of this project, Dr. Dubé is leading a study of vitamin D supplementation to preserve bone health in this
population. He was just awarded a new 4-year CCTG grant that will focus on PrEP in transgender persons. He is
also an active member of the AIDS Clinical Trials Group and is protocol co-chair for the ongoing ACTG 5346 study
“A Randomized, Blinded Placebo-Controlled Trial of a Dipeptidyl Peptidase-4 Inhibitor (Sitagliptin, Januvia) for
Reducing Inflammation and Immune Activation in HIV Infected Men and Women”.
P. Jan Geiseler, MD
Dr. Geiseler continued his role as Co-Investigator in ACTG and CCTG studies that
evaluate antiretroviral therapy utilizing new treatment and prevention strategies for
patients infected with HIV. Dr. Geiseler was the USC PI for two important ACTG
trials, A5175 and A5202, which evaluated the efficacy of once daily protease inhibitor
and once daily non-nucleoside reverse transcriptase inhibitor-containing therapy in
combination with nucleoside analogues. These studies resulted in impact bearing
publications. More recently he has been working with ID fellows and colleagues
in other departments to investigate how to better manage patients with transplant
infections.
Brenda E. Jones, MD
Dr. Jones is the USC Principal Investigator of the tuberculosis (TB) diagnostic study, “Evaluation of the 4th
Generation Quantiferon TB Test (CST001) for the Detection of Tuberculosis Infection” (Cellestis, Qiagen NV,
the Netherlands). The 4th Generation Quantiferon TB test aims to further increase the sensitivity of the assay
in immunocompromised patients as well as to possibly aid in differentiating latent TB infection from active TB
disease. Dr. Jones will also investigate Mycobacterium Tuberculosis CD8 cell response as a surrogate marker for TB
treatment response. Dr. Jones is a co-investigator of the NIH R01 proposal entitled, “Integrated Cost-Effective Point
of Care Nucleic Acid Testing for TB Diagnosis” (PI: Niemz, Keck Graduate Institute, Claremont), which received
an impact score of 29. Future collaborative studies on TB diagnostics are planned.
Dr. Jones was co-investigator with Dr. Michael Neely (PI), Department of Pediatrics at Children’s Hospital Los
Angeles, for the NIH funded “Prospective Study to Optimize Vancomycin Dosing in Children and Adults using
Multiple-Model Bayesian Adaptive Control.” The finding that vancomycin troughs were not adequate for optimal
dosing in 90 patients enrolled at LAC+USC was submitted for presentation. Dr. Jones also participated in the
International Food Information Council (IFIC) Foundation Physicians Roundtable on Antibiotic Resistance.
Paul D. Holtom, MD
Dr. Holtom is Director of the Jeanette Wilkins Memorial Microbiology Laboratory. He collaborates with faculty in
the Department of Orthopaedic Surgery on clinical studies of new treatment strategies for bone and joint infections.
These studies include evaluation of new antimicrobials for skin and soft-tissue infections and in vitro and in vivo
studies on local antibiotic therapy and the elution of antibiotics from PMMA beads and spacers. Dr. Holtom also
conducts studies with ID fellows on the epidemiology of nosocomial bacterial infections and invasive candidal
disease.
72
Department of Medicine 2015
Fred R. Sattler, MD
In addition to serving as PI of the USC ACTG grant, Dr. Sattler recently served on a NIAID Task Force that
was ordered by the President to design the first therapeutic trials to study new treatments of H1N1 and seasonal
influenza. In the ACTG, Dr. Sattler is voting member of the Inflammation and End Organ Transformative Sciences
Group. He is also a member and facilitator for the Immune Activation Focus Group and Co-Chair of the Exercise
Focus Group. In addition, Dr. Sattler (PI) along with collaborators at University of California, San Diego showed
that neurocognitive dysfunction in patients with HIV is aggravated by abdominal obesity and mediated by systemic
inflammation and is associated with CNS activation of microglial cells. The latter studies results in his obtaining
an R01 grant to evaluate the growth hormone releasing factor (Tesamorelin) to assess its efficacy in increasing the
powerful IGF-1 brain neurotroph and reducing visceral adipose tissue in abdominally obese HIV infected patients
with neurocognitive impairment. Dr. Sattler also has two foundation grants to study the effects of sitagliptin for
suppressing macrophage activation in abdominal adipose tissue and its effects on proatherogenic mediators. Finally,
Dr. Sattler was recently honored by a request from the editorial board of Elsevier to write a peer-reviewed overview
on growth hormone in the aging male for Best Practices & Research: Clinical Endocrinology & Metabolism.
Brad Spellberg, MD
Dr. Spellberg’s NIH-funded research interests are diverse, ranging from basic immunology and vaccinology, to
pure clinical and outcomes research, to process improvement work related to delivery of care, focusing on safety
net hospitals. Dr. Spellberg is currently working on the immunology, vaccinology, and host defense against highly
resistant Gram negative bacilli, including Acinetobacter and carbapenem-resistant Enterobacteriaceae infections.
He has an active discovery and development program that has been NIH-funded for monoclonal antibodies targeting
A. baumannii. He also is working on the pathogenesis of these infections, including
the interface between diabetes, inflammation, and iron. He has an NIH-funded
translational program evaluating transferrin as a potential therapeutic agent to treat
infections and reduce the frequency of emergence of antibiotic resistance. His lab also
has an NIH grant to evaluate a multi-valent antigen approach to vaccination for
S. aureus infections. He has several clinical research projects in development, funded
by NIH, including a randomized trial of fosfomycin therapy for complicated urinary
tract infections which is in protocol development, and an adaptive, platform trial to
enable superiority trials to be conducted for highly resistant Gram negative bacilli,
which is in the design phase. The over-arching theme of the work in his lab is to
understand the pathogenesis of infections caused by highly resistant bacteria, as well
as fungi, with an intent to develop immune-modulatory therapeutic interventions to
improve morbidity and mortality of these infections.
Darren W. Wong, MD
Darren Wong is a new junior faculty member in the Division of Infectious Diseases. He is actively involved in
infection control and antimicrobial stewardship, and integrating both programs to optimize clinical care.
Dr. Wong has initiated research examining empiric gram negative therapy for sepsis with the goal of improving
risk stratification to identify patients with potential drug resistant pathogens, optimizing empiric antimicrobial
therapy, and integrating these findings into the existing antimicrobial stewardship program. He is also the Principal
Investigator in the consortium on resistance against carbapenems in Klebsiella pneumoniae (CRACKLE) an NIH
and Antibiotic Resistance Leadership Group funded multi-center national study analyzing the epidemiology and
regional resistance patterns of these extensively-drug resistant bacterium. He is, under the mentorship of
Dr. Brad Spellberg, participating in the FOCUS trial, examining the efficacy the potential role of fosfomycin for
new treatment indications. Future plans include serving as an investigator for phase 3 clinical trials of experimental
antimicrobial therapeutic agents and resuming Clostridium difficile clinical research, an area of his research prior to
joining the USC faculty.
73
Keck School of Medicine of USC
Division Hightlights
Highlighted Publications
The Division of Infectious Diseases published 22 papers in peer-reviewed journals during the period of January 1
through December 31, 2015, and seven are in press. Five publications are highlighted below:
Dubé MP, Komarow L, Fichtenbaum CJ, Cadden JJ, Overton ET, Hodis HN, Currier JS, Stein JH: Extended
Release Niacin vs. Fenofibrate in HIV-Infected Participants with Low HDL Cholesterol: Effects on Endothelial
Function, Lipoproteins, and Inflammation. Clin Infect Dis 61:840-9, 2015.
Low levels of high-density lipoprotein cholesterol (HDL-C) are common in individuals with human
immunodeficiency virus (HIV) infection, persist during antiretroviral therapy (ART), and are associated with
increased cardiovascular disease (CVD) risk. Virologically controlled participants without CVD on stable ART
with low HDL-C (men <40 mg/dL, women <50 mg/dL) and triglycerides >150 mg/dL were randomized to receive
open-label extended-release niacin 1500 mg/day with aspirin 325 mg/day or fenofibrate 200 mg/day for 24 weeks.
The primary endpoint was the week 24 within-arm change in brachial artery flow-mediated dilation (FMD) in
participants with complete follow-up scans. Of 99 participants, 74 had complete data (35 niacin, 39 fenofibrate).
Median age was 45 years, 77% were male, median CD4(+) count was 561 cells/µL, and brachial FMD was 4.2%.
Median HDL-C was 32 mg/dL for men and 38 mg/dL for women, low-density lipoprotein cholesterol was 103 mg/
dL, and triglycerides were 232 mg/dL. In men, HDL-C increased a median of 3 mg/dL with niacin and 6.5 mg/
dL with fenofibrate (P < .001 for both). In women, HDL-C increased a median of 16 mg/dL with niacin and 8 mg/
dL with fenofibrate (P = .08 for both). After 24 weeks, there was no significant change in FMD in either arm; the
median (interquartile range) change was +0.6% (-1.6 to 2.3) with niacin (P = .28) and +0.5% (-1.0 to 3.0) with
fenofibrate (P = .19). Neither treatment significantly affected C-reactive protein, interleukin 6, or D-dimer levels.
Despite improvements in lipids, niacin or fenofibrate treatment for 24 weeks did not improve endothelial function or
inflammatory markers in participants with well-controlled HIV infection and low HDL-C.
Berbari EF, Souha SK, Kowalski TJ, Darouiche RO, Widmer AF, Schmitt SK, Hendershot EF, Holtom PD,
Huddleston III PM, Petermann GW, Osmon DR: 2015 Infectious Diseases Society of America (IDSA) Clinical
Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clin Inf Dis
61:e26-46, 2015.
These guidelines are intended for use by infectious disease specialists, orthopedic surgeons, neurosurgeons,
radiologists, and other healthcare professionals who care for patients with native vertebral osteomyelitis (NVO).
They include evidence and opinion-based recommendations for the diagnosis and management of patients with
NVO treated with antimicrobial therapy, with or without surgical intervention.
Villarino ME, Scott N, Weis SE, Weiner M, Conde MB, Jones B, Nachman S, Oliveira R, Moro R, Shang N,
Sterling TR, the International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT), and the
Tuberculosis Trials Consortium (TBTC): New Treatment for Preventing Tuberculosis in Children: A Three Month
(12 – Dose) Regimen of Rifapentine and Isoniazid. JAMA Pediatrics 169(3):247-55, 2015.
Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis
infection is safe and effective for persons 12 years or older. Published data for children are limited. To compare
treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and
isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children. A pediatric cohort nested
within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with
follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China),
and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis
infection. Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional,
for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.
We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and
deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%.
Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness.
The noninferiority margin was 0.75%. Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness.
Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazidonly group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to
0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took
the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any
74
Department of Medicine 2015
hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group
developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74%
and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion. Treatment
with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of
tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate
than did the isoniazid-only group and was safe.
Sattler F, He J, Letendre S, Wilson C, Sanders C, Heaton R, Ellis R, Franklin D, Aldrovandi G, Marra CM, Clifford
D, Morgello S, Grant I, McCutchan JA: Abdominal Obesity Contributes to Neurocognitive Impairment in HIV
Infected Patients with Increased Inflammation and Immune Activation. JAIDS 68(3):281-8, 2015.
We tested our hypothesis that abdominal obesity when associated with increased levels of systemic and central
nervous system immunoinflammatory mediators contributes to neurocognitive impairment (NCI). One hundred
fifty-two patients with plasma HIV RNA <1000 copies per milliliter had clinical evaluations and cognitive function
quantified by global deficit scores (GDS). GDS, waist circumference (WC) and plasma IL-6, sCD163, and sCD14
and CSF sCD40L, sTNFrII, MCP-1, sICAM, and MMP-9. WC and plasma IL-6 levels positively correlated with
GDS; the WC correlation was strongest in the high tertile of IL-6 (ρ = 0.39, P = 0.005). IL-6 correlated with GDS
only if WC was ≥99 cm. In the high tertile of CSF sCD40L, a biomarker of macrophage and microglial activation,
the correlation of IL-6 to GDS was strongest (ρ = 0.60, P < 0.0001). Across 3-5 visits within ±1 year of the index
visit, GDS remained worse in patients with IL-6 levels in the high versus low tertile (P = 0.02). Path analysis to
explore potential mediators of NCI produced a strong integrated model for patients in the high CSF sCD40L tertile.
In this model, WC affected GDS both directly and through a second path that was mediated by IL-6. Inclusion of
plasma sCD14 levels strengthened the model. NCI was more common in men and for individuals with components
of the metabolic syndrome. Neurocognitive function was significantly linked to abdominal obesity, systemic
inflammation (high IL-6), and immune activation in plasma (high sCD14) and CSF (high sCD40L). Abdominal
obesity, inflammation, and central nervous system immune activation are potential therapeutic targets for NCI in
HIV-positive patients.
Spellberg B, Bartlett JG, Wunderink R, Gilbert DN: Novel Approaches Are Needed to Develop Tomorrow’s
Antibacterial Therapies. Am J Resp Crit Care Medicine 191:135-40, 2015.
Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up.
Antibiotics are a public trust; every individual’s use of antibiotics affects their efficacy for everyone else. As such,
responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a
combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and
a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics.
More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that
modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance
emergence. Economic transformation will require new business models to support antibiotic development. Finally,
regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant.
Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective
antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic
therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable
viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.
75