What’s New in Infectious Diseases? Bruce L. Gilliam, M.D. Institute of Human Virology University of Maryland School of Medicine Baltimore, MD Topics New Antibacterial Therapeutics Emerging Pathogens HIV Hepatitis C Disclosures Research Studies Pfizer – Staph aureus Vaccine Trial TaiMed Biologics - Ibaluzimab Advisory Board Viiv Healthcare New Antibacterial Therapeutics • Dalbavancin • Oritavancin • Tedizolid • Ceftolozane/tazobactam • Ceftazidime/avibactam • Fecal Transplant Incidence of Staph aureus hospitalizations in U.S.A., 2001–2009 BMC Infect Dis 2014, 14:296 Dalbavancin (Dalvance) • Derived from Teicoplanin • ½ life – Effective: 8.5 days – Terminal: 346 hrs (14 days) • Bactericidal • Similar spectrum to Vancomycin, active against: – Staphylococci • MSSA, MRSA, CoNS – Streptococci • resistant pneumococci • anaerobic strep – Enterococci • VRE with van B, C but not A – Corynebacterium Dalbavancin Once Weekly Non- Inferior to Vanco/Linezolid N Engl J Med 2014;370:2169-79. Single-Dose (1.5 g) Non-Inferior to Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection 100 90 80 70 60 50 Single Dose 40 Once Weekly 30 20 10 0 Overall Clinical Success Rate Success Rate Success Rate Response Day 14 Day 28 Day 14 MRSA Clin Infect Dis. 2015 Nov 26. pii: civ982. [Epub ahead of print] VA Experience with Dalbavancin • Background – Levels in bone > MIC for 14 days • 8 patients treated for osteomyelitis with IV Dalbavancin – Former IV drug users not eligible for home IV or unwilling to do home IV • Treated for up to 8 weeks • No adverse events • All with resolution of osteomyelitis • Cost savings vs. placement in facility Oritavancin (Orbactiv) • Derived from Vancomycin • ½ life – Terminal 245-393 hrs (10-16 days) • Bactericidal • Similar spectrum to Vancomycin, active against: – Staphylococci • MSSA, MRSA, CoNS – Streptococci • resistant pneumococci • anaerobic strep – Enterococci • VRE with van A, B, C – Corynebacterium Single Dose Oritavancin vs. Vancomycin in Acute Bacterial Skin Infections N Engl J Med 2014;370:2180-90. Should I use Dalbavancin or Oritavancin Dalbavancin Oritavancin • Short infusion: 30 min • Active against van A • Active against catheter enterococci related BSI • Few drug-drug • Long infusion: 3 hrs interactions – Infusion reaction if shorter • pK data in bone, tissue • Drug-drug interactions – 31% increase warfarin • Can prolong PTT and CT – No heparin within 48 hrs Tedizolid (Sivextro) • Oxazolidinone antibiotic • Prodrug • pK – ½ life 12 hrs – Once daily – >90% oral bioavailable • Bacteriostatic – Cidal in animal models • Not expected to have MAOI interactions • Microbiology – Staphylococci • MSSA, MRSA, CoNS – Streptococci • resistant pneumococci • anaerobic strep – Enterococci – Corynebacterium – Atypical mycobacteria Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections 100 90 80 70 60 50 Tedizolid 40 Linezolid 30 20 10 0 Early Response Sustained Response Investigator Treatment Success JAMA. 2013;309(6):559-569 Should I use Tedizolid or Linezolid Tedizolid Linezolid • Once daily • Now generic so lower • 6 days for ABSSSI cost • Potentially • Twice daily – Less MAOI interaction • 10 days for ABSSSI – Less hematologic effects • Interaction with MAOI • May be active against some linezolid resistant • Hematologic effects strains • Possible accumulation of • No dose adjustment in metabolites in renal hepatic or renal failure Numbers of carbapenemase-producing Enterobacteriaceae referred to the UK national reference laboratory – 2003- 2009 Lancet Infect Dis 2010; 10: 597–602 New Agents to Treat GNRs Ceftolozane Ceftazidime Tazobactam Avibactam Drugs. 2013 Feb;73(2):159-77. Pharmacotherapy. 2015 Aug;35(8):755-70. Pharmacotherapy. 2015 Jul;35(7):701-15. Ceftolozane/Tazobactam(Zerbaxa) • 1.5g (1g Ceftolozane 0.5g Tazobactam) every 8 hours – Needs renal adjustment • FDA approved for – Complicated urinary tract infections – Complicated intra-abdominal infections • Broad spectrum gram negative activity including – Pseudomonas aeruginosa (including MDR strains) – Some extended-spectrum beta-lactamases (ESBL) from the TEM-1 & 2, SHV, CTX-M and OXA groups – NOT active against organisms that produce serine carbapenemases (eg., KPCs) and metallo-beta lactamases • Other activity includes the Streptococcus milleri group (S. anginosus, S. constellatus, S. intermedius) and Bacteroides fragilis Ceftazidime/Avibactam (Avycaz) • 2.5 gm (2 gm ceftazidime, 0.5 gm avibactam) over 2 hours every 8 hours – Renal dose adjustments required • FDA approved for – Complicated urinary tract infections – Complicated intra-abdominal infections • Avibactam is a potent inhibitor of class A, class C and some class D beta-lactamases • Broad spectrum gram negative activity including Enterobacteriaceae including ESBLs (TEM, SHV, CTX- M) and KPC producers, and Pseudomonas – Minimal anaerobe coverage, high MICs for B. fragilis • Note - avibactam does not restore the activity of ceftazidime against P. aeruginosa as reliably as it does Enterobacteriaceae (likely due to other mechanisms of resistance such as porin alterations, efflux pumps, metallo-β-lactamases or OXA β-lactamases) When to use the GNR antibiotics • Ceftolozane/tazobactam • Ceftazidime/avibactam – FDA approved – FDA approved • UTI • UTI • cIAI • cIAI – Being studied in VABP – Being studied in VABP – Renal adjustment – Renal adjustment – Use – Use • MDR Pseudomonas • MDR Pseudomonas • Some ESBLs • ESBLs • Not active against KPC • Active against KPC – Cost $$$ – Cost $$$$$ • Need to check susceptibilities for use Incidence of Nosocomial Clostridium difficile Infection N Engl J Med 2015;372:1539-48. Antibiotic Classes and Their Association with Clostridium difficile infection • Careful use of antibiotics can make a difference – antimicrobial stewardship N Engl J Med 2015;372:1539-48 Treatment of Clostridium difficile infection N Engl J Med 2015;372:1539-48 Rates of Cure and Changes to the Microbiota after Fecal Microbial Transplantation for Recurrent Clostridium difficile Infection. N Engl J Med 2015;372:1539-48 Emerging Pathogens • Ebola • Zika • Chikungunya • Borrelia miyamotoi Ebola Virus • Filovirus • Clinical – Fever, severe headache, muscle pain, weakenss, fatigue, diarrhea, vomiting, abd pain, unexplained hemorrhage (bleeding or bruising) – Incubation: 8-10 days(range 2-21 days) – Mortality rate: 25-90% Ebola What Did We Learn • Ebola virus disease survivors frequently reported anorexia and arthralgia • Persistence – Semen – detected 284 days after symptoms – Aqueous humour – detected 9 weeks after recovery – Vaginal fluids, sweat, urine, and breast milk – CNS symptoms 9 months after recovery • Can be sexually transmitted • Transfusion of plasma from convalescent donors did not improve survival – Neutralizing Ab levels not checked • Patients receiving Artesunate-amodiaquine had a 31% lower risk of death than those receiving artemether-lumefantrine N Engl J Med. 2016 Jan 7;374(1):33-42 N Engl J Med. 2015 Jun 18;372(25):2423-7. BMJ Open. 2016 Jan 7;6(1):e008859 N Engl J Med. 2016 Jan 7;374(1):23-32 Int J Infect Dis 2016; 43; 58-61 N Engl J Med. 2015 Oct 14 N Engl J Med. 2015 Dec 17;373(25):2448-54 Ebola What Did We Learn • Multilevel, interprofessional collaboration to isolate HID cases and reduce disease transmission will be crucial to contain future outbreaks1 • Potential therapies – Virus-neutralizing antibody cocktail (ZMab) – Vesicular stomatitis virus-vectored Ebola glycoprotein vaccine (rVSV/ZEBOV-GP) – T-705 (favipiravir) - nucleotide analog – BCX4430 – nucleoside analogue 1. Infect Control Hosp Epidemiol. 2015 Dec 8:1-6. [Epub ahead of print] Zika Virus • Arbovirus • First isolated in Zika Forest Uganda 1947 • Transmitted by Aedes mosquito • Incubation: 3-12 days • Symptoms: mild fever, arthralgia (small joints of hands and feet), myalgia, HA, asthenia, abdominal pain, edema, lymphadenopathy, retro-orbital pain, conjunctivitis, and cutaneous maculopapular rash • Largely limited to Africa and Asia until 2015 when spread to Brazil, Columbia, Venezuela, Mexico • Now cases in Puerto Rico, Texas, Hawaii Distribution of Zika Virus http://www.cdc.gov/zika/geo/index.html Zika Virus in Travelers returning from the Cook Islands • Conjunctivitis and Rash Clin Infect Dis. 2015; 61 (9): 1485-1486 Zika vs. Dengue • Conjunctivitis – 17/31 [55%] of ZIKA patients vs 14/148 [9%] DENGUE patients • Absence of thrombocytopenia • Rash – more common in ZIKA – 28/31 [90%] ZIKA patients [5] vs 44/148 [30%] DENGUE patients Clin Infect Dis. 2015; 61 (9): 1485-1486 Zika Virus Why is it Important • Largely limited to Africa and Asia until 2015 when spread to Brazil, Columbia, Venezuela, Mexico • Now in Puerto Rico, Texas, Hawaii – Texas case in traveler from El Salvador – Local transmission reported in Samoa, Puerto Rico, Mexico, Carribbean, Central and South America • Linked to – Microcephaly in pregnant women with infection • 1200-4000 cases in Brazil(up from 150-200) coincident with outbreak • Brazilian government recommending that mothers delay conception – Guillain-Barre syndrome • What can you do – Mosquito control/avoidance – No treatment • Test Pregnant women for Zika in consult with health dept if – history of travel to an area with Zika virus transmission – and 2+ symptoms consistent with Zika virus disease during or within 2 weeks of travel • acute onset of fever, maculopapular rash, arthralgia, or conjunctivitis – or have US findings of fetal microcephaly or intracranial calcifications • All pregnant women consider postponing