conflict of interest · 3/7/2019 4 antibiotics who •antimicrobial resistance (amr) threatens the...

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Infectious Disease Update“Its Been a Busy Year”

TED ROSEN, MDPROFESSOR OF DERMATOLOGYBAYLOR COLLEGE OF MEDICINEHOUSTON, TEXAS

Conflict of Interest

NONE

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Frank Burnet, MD, PhD Nobel Prize in Medicine, 1960

“One can think of the middle of the twentieth century as the end of one of the most important social revolutions in history, the virtual elimination of the infectious diseases as a significant factor in social life” -1961

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It’s probably SARS,

West Nile virus, HIV,

H1N1 flu, Monkeypox,

MRSA, Pan-resistant

Neisseria gonorrhea,

Chikungunya, Zika,

MDR TB or Ebola

•Big Trends:

•Antibiotic resistance: Threat to mankind

• New antibiotics!

•New anti-infectives for exotic diseases

•Epidemiologic shifts: Some diseases “in” and some “out”

•STDs, especially syphilis, are resurgent

•Vaccines hold great promise

•Unexpected sources for infectious diseases!

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Antibiotics

WHO

• Antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever-increasing range of infections, particularly those caused by bacteria

• Without effective antimicrobials, medical procedures such as organ transplantation, cancer chemotherapy, diabetes management and major surgery become very high risk.

http://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance: Accessed 11-16-2018

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Public’s Antibiotic IQ Low!

• 11.5 million prescriptions for oral antibiotics and 6.9 million prescriptions for topical antibiotics were dispensed for dermatology related issues, mostly acne, in USA

• CDC Survey >800 acne patients and >200 parents acne patients

• 67% were unaware that antibiotic-free regimen could be used

• 64% were unaware that antibiotic use could lead to carrier state of antibiotic resistant bacteria

• 50% had not discussed antibiotic risk with HCP

http://www.cdc.gov/media/dpk/2015/dpk-antibiotics-week-2015.html

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Oct 1, 2013

“Dermatologists comprise about 1% of

all US physicians, but prescribe over 5%

of all antibiotics.”

Good News!• Retrospective claims data (Optum)

• 2008-2016: 985,866 courses of oral antibiotics prescribed by 11,986 unique dermatologists

• DECREASE 3.36 Abx per 100 visits to 2.13 Abx per 100 visits over time

• Post-surgical use, however, rose from 2.73 to 3.92/100 visits

• May put patients at unnecessary risk of adverse events and/or develop and harbor resistant microbes

JAMA Dermatol. 2019 Jan 16. doi: 10.1001/jamadermatol.2018.4944

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Take Home Messages…..

•Use antibiotics wisely

•Know what you are treating

•Don’t use antibiotics “just in case”

•Proper dose and duration

•Have an exit strategy!

•Advise patients on proper antibiotic use

ANTIBIOTIC MOA INDICATION CLASS COMMENT

Delafloxacin 6-17 DNA replication Broad spectrum, MRSA Quinolone Reduced toxicity

Omadacycline 10-18 Protein synthesis Broad spectrum, MRSA Aminomethylcycline ↓Resistance; QD

Sarecycline 10-18 Protein synthesis Acne Tetracycline Narrow spectrum

Ozenoxacin 12-17 DNA replication Impetigo: Strep, Staph Quinolone Topical; BID x 5d

Oritivancin Cell wall formation ABSSI, MRSA Lipoglycopeptide Single dose = Rx

Dalbavancin Cell wall formation ABSSI, MRSA Lipoglycopeptide Single dose = Rx

Tedizolid Protein synthesis ABSSI, MRSA Oxazolidinone QD dosing

Ceftaroline Cell wall formation ABSSI, MRSA Cephalosporin BID dosing

Relatively new FDA-approved antibiotics

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New Antibiotic: Sarecycline

• Chemical class: tetracycline

• MOA: Binds 30S ribosomal subunit, no AA-tRNA attachment

• Inhibits protein synthesis

• Also anti-inflammatory in nature

• Narrow spectrum activity

• Includes: C. acnes, S. aureus; Minimal vrs Gr- enteric bacteria

• Available: Oral only (unit doses: 60mg, 100mg, 150mg)

• Once daily dosing weight-based: 1.5mg/kg x 12 weeks

• Resistance: Can occur; Nausea, headache: 3%; Yeast <1%

Antimicrob Agents Chemother. 2018 Nov 5. pii: AAC.01297-18J Drugs Dermatol. 2018 Mar 1;17(3):333-338.

Sarecycline • Two parallel Phase 3 studies

• N=1002 (saracycline) and 1000 (placebo)

• QD x 12 week

• IGA: 2 grade improvement; clear/almost

• Saracycline: 21.9% and 22.6%

• Placebo: 10.5% and 15.3%

• ~50% reduction number inflammatory lesions at therapy end (12 weeks), whereas placebo showed ~35% reduction

• Vestibular AEs <1% Photosensitivity <1%

J Drugs Dermatol. 2018 Sep 1;17(9):987-996

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New Antibiotic: Omadacycline

• Chemical class: Aminomethylcycline

• MOA: Binds 30S ribosomal subunit, no AA-tRNA attachment

• Inhibits protein synthesis

• Wide spectrum activity Gr+ / Gr- organisms; anaerobes

• Includes: MRSA, Strep pyogenes, VRE, Legionella, Chlamydia

• Available IV (unit dose 100mg) and Oral (unit dose 150mg)

• QD dosing after loading: IV 200mg->100mg; PO 450mg x 2 d->300mg

• Resistance: Uncommon (evades efflux and ribosomal protection)

• Status: Approved ABSSSI in October, 2018 Ann Clin Microbiol Antimicrob. 2016;15(1):34-36J Antimicrob Chemother. 2017;72:3471-3480

Omadacycline vrs Linezolid in ABSSSIs

https://clinicaltrials.gov/ct2/show/NCT02877927

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Utility?

Erysipelas/Cellulitis

Wound Infection Abscess

NOT effective against Eikenella (human bites) but otherwise very good

Antimicrob Agents Chemother. 2018 Mar 27;62(4). pii: e02551-17. doi: 10.1128/AAC.02551-17

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Pet Bites! Think Omadacycline!

New antibiotic: Ozenoxacin

• Chemical class: Non-fluorinated quinolone

• MOA: Blocks topoisomerase II and DNA gyrase

• Inhibits bacterial DNA replication

• Developed as 1% cream for impetigo

• Dosed: BID x 5 days

• Wide spectrum of activity against relevant Gram+ microbes, including MSSA, MRSA, mupirocin and ciprofloxacin resistant Staphylococci, Strep. pyogenes

• Superior to placebo, and non-inferior retapamulin**• Microbiological effect in as little as 2 days**

• N=875 in two international studies, age > 2 months

• Status: Approved for impetigo: 12-14-2017J Drugs Dermatol. 2018 Oct 1;17(10):1051-1057JAMA Dermatol. 2018 Jul 1;154(7):806-813

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J Drugs Dermatol. 2018 Oct 1;17(10):1051-1057

JAMA Dermatol. 2018 Jul 1;154(7):806-813

Utility?

Do we need another agent?

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Why Is New Impetigo Drug Important?

•High level resistance to mupirocin reported (~60%)

•Conjugative (mupA) and nonconjugative (mupB) genes in Streptococci & Staphylococci confer resistance (encode for alternate isoleucyl-tRNAsynthetases)

•Mupirocin resistance is a worldwide phenomenon: recent papers from China, France, India, Chicago

Microbiol Spectr. 2018 Jan;6(1). doi: 10.1128/microbiolspec

ANTIBIOTIC MOA INDICATION CLASS COMMENT

Lefamulin Protein synthesis ABSSI, MRSA Pleuromutilin Minimal resistance

Iclaprim DNA/RNA synthesis MRSA Diaminopyrimidine Minimal resistance

Contezolid Protein synthesis All gram+, MRSA Oxazolidinone Safer than Linezolid

Ph 3 Done Awaiting approval

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ANTIBIOTIC MOA INDICATION CLASS COMMENT

Lefamulin Protein synthesis ABSSI, MRSA Pleuromutilin Minimal resistance

Iclaprim DNA/RNA synthesis MRSA Diaminopyrimidine Minimal resistance

Contezolid Protein synthesis All gram+, MRSA Oxazolidinone Safer than Linezolid

Gepotidacin DNA replication Gonorrhea Triazaacenaphthylene Single 1.5g dose = Rx

Zoliflodacin DNA replication Gonorrhea Spiropyrimidinetrione Single 2g dose = Rx

Solithromycin Protein synthesis Gonorrhea Fluoroketolide Single 1g dose = Rx

ANTIBIOTIC MOA INDICATION CLASS COMMENT

Lefamulin Protein synthesis ABSSI, MRSA Pleuromutilin Minimal resistance

Iclaprim DNA/RNA synthesis MRSA Diaminopyrimidine Minimal resistance

Contezolid Protein synthesis All gram+, MRSA Oxazolidinone Safer than Linezolid

Gepotidacin DNA replication Gonorrhea Triazaacenaphthylene Single 1.5g dose = Rx

Zoliflodacin DNA replication Gonorrhea Spiropyrimidinetrione Single 2g dose = Rx

Solithromycin Protein synthesis Gonorrhea Fluoroketolide Single 1g dose = Rx

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Antimicrob Agents Chemother. 2018 Sep 24. pii: AAC.01221-18.

MoreTherapeutics

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Tecovirimat (TPOXX®)

July 13, 2018

The OMG!• USA stopped administering Smallpox vaccine in 1972

• Smallpox deemed “eradicated” by WHO/CDC in 1980

• However, it is still used in biological warfare research

• HIGH MORTATLITY RATE ANTICIPATED IF WEAPONIZED

• No therapy…..until now!

• New drug: Tecovirimat (po) [a.k.a. ST-246] TPOXX®

• Unit dose: 200mg capsules; Weight-based dosing

• 13 kg to less than 25 kg: 200 mg twice daily for 14 days

• 25 kg to less than 40 kg: 400 mg twice daily for 14 days

• 40 kg or more: 600 mg twice daily for 14 days

•Already stockpiled!!!!!

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August 29, 2017

Benznidazole (No brand name) 8-2017

• Rx children 2-12 (and adults) w/ Chagas disease (acute or chronic)

• Parasitological cure better: younger age and acute disease (vrs chronic) 60-90%

• Destroys parasite DNA

• 5-8 mg/kg/d (divided doses) x60d

• 12.5 and 100mg tablets

• Peripheral neuropathy

• Bone marrow depression

• Hypersensitivity reactionsJ Antimicrob Chemother 2018;73:1060-67

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Chagas Disease

Chagas Disease in USA?

• Rare indigenous cases

• 6 US Reduviid (Triatome) species

• T. gerstaeckeri, T. indictivaT. lecticularia, T. protractaT. rubida and T. sanguisuga

• Survey of 1510 US vectors, 54.4% harbored T. cruzi, including subtypes known to cause Chagas disease

•Texas, LA, FL, NM, AZInfect Genet Evol. 2017;58:171-180

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The Truly Obscure

LANCET 2018;39 2:1 207

•Onchocerciasis (River Blindness)

• Rx of choice: Ivermectin

• But repeated Q2mo….10 years!

• Moxidectin: longer T1/2, Better results; 8mg (4 x 2mg)

• Study of 1400 patients, in 3 African countries

• FDA Approved June, 2018

LANCET 2018;391 : 144

•African Trypanosomiasis

• Rx of choice: Nifurtimox-Eflornithine

• But very toxic

• Fexinidazole: As effective, Few AEs 1800mg (Days 1-4) 1200mg (Days 5-10)

• Study of 794 patients in 2 African countries

• EMA approved November, 2018

Pediculosis Capitis

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Head Lice in Young Adults!!!!!

Selfie Craze!

Pediculosis capitis (Head lice)

• Collected head lice: 138 sites, 48 states

• Excluded Alaska and West Virginia

• Summer 2013-Summer 2015

• 96% of sites had 100% of all lice carrying resistance genes to pyrethroids

• 42 states had 100% resistance of all lice

• Correlates w/ Rid® & Nix® brand failures

J Med Entomol 2016;53:653-659

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Hyperthermia and Head Lice

•AirAllé® (Formerly called Louse Buster®)

•Hot air instrument used in special clinics; Exposure is about 30 min

•Followed by nit picking for 30-60min

•Cost varies $85-175 per session

•99% pediculocidal and ovicidal

Pediatrics. 2006;118:1962–70

Abametapir• Abametapir 0.74%

• Blocks metalloproteinases

• Prevents egg from opening (no nymphs)

• Interferes w/ vital enzymes in adults

• Ovicidal and Pediculocidal

• Single 10 minute application; Age > 6 months

XJ Med Entomol. 2017;54:167-172

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Abametapir Efficacy: Primary & Secondary Endpoints

Primary: Day 14 Secondary: Days 1 and 7

Pediatr Dermatol. 2018 Sep;35(5):616-621

Epidemiology

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What Happened to the Arbovirus Threat?

Chikungunya• Fever, arthralgia/myalgia, headache, maculopapular rash

• 2006-2013 average ~30 US people; returning travelers from Africa, Asia, Indian Ocean

• 2014: Local cases in Puerto Rico, Caribbean and Florida (12) Total USA cases 2811

• 2015: One local case in Texas; Total USA cases 896

• 2016: NO local cases in USA; Total USA cases 248

• 2017: NO local cases in USA; Total USA cases 104Only 33 local cases in PR

• 2018: NO local cases in USA; Total USA cases 90

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Zika• Fever, arthralgia/myalgia, headache, maculopapular

eruption, conjunctivitis; babies: microcephaly, eye & CNS problems

https://www.cdc.gov/zika/reporting/case-counts.html

Confirmed Zika cases, USA

2018: 64 total casesNo local

452 total7 Local (TX)

5168 total224 Local (FL)

Zika: Thinking Outside The Box

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Zika: A Hero?

• Zika virus infection ASx in 80%+ of those infected

• Zika virus attacks immature neurons

• Unaltered Zika virus DESTROYS HUMAN TUMORS consisting of immature neurons (Neuroblastoma and gliobastoma)

• (CD24 expression essential for effect)

• Now being investigated in mammalian animal models

PLoS One. 2018 Jul 25;13(7):e0200358 J Exp Med. 2017 Oct 2;214(10):2843-2857

PLoS One. 2018 Jul 25;13(7):e0200358

J Exp Med. 2017 Oct 2;214(10):2843-2857

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Just when you think its safe…..!

Mother Nature Balances the Scorecard

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Yellow Fever Outbreak in….Brazil

• 10 Travel-related cases

• Travel to USA home from Brazil

•4 of 10 died

• None received YF vaccine (Single dose lifelong immunity)

• CDC and WHO recommends vaccine for travelers to Bahia, Sao Paulo, Rio de Janeiro, Espirito Santo states

MMWR 2018;67:340

Yellow Fever

https://www.cdc.gov/yellowfever/maps/south_america.htmlhttps://www.cdc.gov/yellowfever/maps/africa.html

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Yellow Fever Flavivirus + Aedes Mosquito vector

August 6, 2018

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West Nile Virus (Fever)• Flavivirus; Vector: CULEX mosquito• Bite at dawn and dusk

• Peak: August, September

• Human being is “dead end” host; Normal hosts are birds (crow)• Watch for dead birds!

• 80% ASx

• 20% Flu-like symptoms; rare morbilliform to purpuric eruption

• <1% meningitis or encephalitis• Confusion, somnolence, headache, coma, death

• No specific therapy; supportive; May be long rehabilitation

• Currently: ALL STATES but New Hampshire/Hawaii reporting WNV 2018

West Nile Virus

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West Nile Virus USA Confirmed CasesYear 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008

Cases 2544 2097 2149 2175 2205 2469 5674 712 1021 720 1356

Neuro 63% 32.0% 39.1% 33.1% 39.0% 48.7% 49.4% 32.7% 38.4% 46.4% 49.1%

USACanada VenezuelaColumbiaArgentina

https://www.cdc.gov/westnile/statsmaps/preliminarymapsdata2018/index.html

My office My car →

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1466-1536

New Recombinant Zoster Vaccine • VZV subunit vaccine for shingles (not live attenuated)

• Glycoprotein E antigen + adjuvant; TWO doses, IM @ 0, 2-6

• ACIP voted to FAVOR this over existing HZ vaccine

• Indicated for use over age 50; EVEN if given prior vaccine

• 90-97% effective across ALL AGES; 4 year study (9yr Ab+)

• 88% overall effective reduction of PHN

• Use in HIV+ inconclusive, although appears positive

• AEs: injection site reactions, systemic side effects

• 16.5% report ANY Gr3 adverse event

• Myalgia, fever, headache, fatigue, shivering, GI distress

MMWR Morb Mortal Wkly Rep. 2018;67:103-108

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Duration 2-3 days

MMWR Morb Mortal Wkly Rep. 2018;67:103-108

Duration 1-2 days

MMWR Morb Mortal Wkly Rep. 2018;67:103-108

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MMWR Morb Mortal Wkly Rep. 2019 Feb 1;68(4):91-94

“Is it safe?” (from Marathon Man, 1976)

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Safety of new zoster vaccine?• Tracked during first 8 months of use

• 3.2 million doses given

• 4381 reported adverse events; 130 serious (3%)

• 7 deaths: 4 CV, 2 septic shock, 1 complications of a fall

• 230 vaccination “errors”: wrong route (SQ instead of IM) and failure to mix two vials and administer mixture

• Fever 24%

• Injection site pain 23%

• Injection site redness 20%

• Findings from early monitoring of RZV are consistent with the safety profile observed in prelicensure clinical trials

MMWR Morb Mortal Wkly Rep. 2019 Feb 1;68(4):91-94

Lancet Infect Dis. 2018;18:162-170

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On the horizon…

Vaccines…..Progress

VIRUSES. 2018 NOV 14;10(11) E -PUB

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Lancet. 2017 Feb 4;389(10068):505-518Lancet Infect Dis. 2017 Dec;17(12):1276-1284

Fungal Vaccines?

• Goal: To improve Th1, Th17 response

• rAls3p-N antigen vaccine (Phase 2b): Candida

• Recombinant Sap2 antigen (Phase 2a): Candida

Front Microbiol. 2017;8:36. Pharm Pat Anal 2016;5:115–134

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• FDA Approved: Dec 21, 2018• Diphtheria, tetanus, pertussis,

poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b

• Ages 6 weeks-4 years• Three IM shots: 2-4-6 months• Apnea in premature babies• Injection site rxn (18-44%),

irritability (55%), crying (44%), somnolence (40%), anorexia (23%), fever (19%), vomiting (9%)

• Available 2020

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Vaccinations and USA• GOOD NEWS (Nationally)

• MMR: 94.3%

• DPT: 95.1%

• Varicella: 93.8%

• BAD NEWS

•Exemption rate continues to rise, 2.2%

• Unvaccinated born 2017=1.3% (2001=0.3%)

•Many children unvaccinated: susceptibleMMWR 2018;67:1115-22

Mumps virus (paramyxovirus)MMR since 1967

Flu-like illness, then swollen salivary glands

Orchitis, Oophoritis

Rare: Meningitis, encephalitis, deafness

Salivary dissemination (kiss, sneeze, cough)

Oct 9, 2018

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Mumps

1-9-2019

https://www.newsweek.com/new-york-hit-worst-measles-outbreak-decades-2019-news-1285778

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Measles, USA 2018

https://www.cdc.gov/measles/cases-outbreaks.html

https://www.who.int/news-room/detail/29-11-2018-measles-cases-spike-globally-due-to-gaps-in-vaccination-coverage

11-29-2018

WHO: Measles cases up 30%

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Measles Outbreaks: Global 2018

• N and S America (2018) 8,091 confirmed cases, including 85 deaths

• Venezuela 5525 (73 deaths)

• Brazil 2192 (12 deaths)

• USA 349 (0 deaths)

• Columbia 129

• Other “hot spots” include Israel, Thailand

FranceGreeceIrelandItaly RomaniaSlovakia

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PR is due to HHV6 or HHV7Retrospective study (Italy)76 Women PR during pregnancyRISK OF COMPLICATION:PR < 15 weeks gestationExtensive eruption ( >50% BSA )Constitutional signs/SxCOMPLICATIONSStillbirthSpontaneous abortionDermatology. 2018;234(1-2):31-36

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Unexpected Source of ID

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And…Bedbugs fly free!

Moral: Don’t eat stuff from the environment!

• 19 year-old Aussie rugby star

• Ate a garden slug on a dare

• Fell ill, developed eosinophilic meningo-encephalitis; coma

• Left a quadriplegic w/ seizures

• Rat lungworm infected slug after the latter ate rat feces (Angiostrongylus cantonensis)

• Man died 8 years later

Lindsey Bever, Washington Post, Nov 5, 2018

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March 28, 2018

NPJ Biofilms Microbes 2018; Mar 24;4:7

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Pathogens You Know and Love

• 61% Pseudomonas aeruginosa

• 33% Legionella pneumophila

• 33% Listeria spp

• 22% Enterococci spp

• 4.8% Klebsiella spp

• 50% had one or more…

• Phialophora spp

• Exophiala spp

• Fusarium spp

NPJ Biofilms Microbes 2018; Mar 24;4:7

Moral To The Story?

No more rubber ducks in the bath!

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Your Host (pun intended)

Ted Rosen, MDProfessor of DermatologyBaylor College of Medicine

Houston, Texas

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