ANTIBIOTIC CHOICES & RESISTANCE: ACP

Alabama/ Mississippi John G. Bartlett, MD

Professor of Medicine, Emeritus

Johns Hopkins School of Medicine, Baltimore

Disclosure of Financial Relationships

John G. Bartlett, MD

Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used

on, patients.

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

Bad bugs-Antibiotic Resistance:History, Current status & MACRA

History: 2004: IDSA- “Bad Bugs, No drugs” 2015: CDC: “Resistance crisis”; We need a plan 2016: WHO: Global resistance crisis US Data: (MMWR 2016;65:235)- US per capita abx use is >2x that of all European countries, but we rank #23-27 for health outcomes- longevity, infant mortality, addiction etc Response: MACRA-CDC (Public Health); CMS (Major payer); Goal: Address abx abuse & improve care or “value” to replace “volume”

CDC: ANTIMICROBIAL USE & RESISTANCE (AUR) Module

Goal: Establish risk-adjusted benchmarks for antimicrobial use by agent, route of treatment (PO, IV, IM) & Days of Therapy (DOT) analyzed by patient units (Medical, Surgery, ICUs, Pediatrics, obstetrics, outpatients, etc) Mo/Yr Drug Total IV IM GI Resp

Location Levo 7 days 4 days 0 3 days 0

The CDC/CMS stewardship plan Requirements: Healthcare facilities receiving CMS funding must have antibiotic stewardship program Leadership:(ID trained MD +/- ID Pharmacist) + $ support Expectations: Audit abx use compared to “benchmarks” Data source: EHR for local & National comparisons Example: FQ use by hospital, specialty, DRG & provider. Note: Dr Woodliff (MS ACP): 93 page review w/recs

Concerns:Computer time, defining “value”, need to engage practitioners, ease of gaming

The CDC/CMS stewardship plan Requirements: Healthcare facilities receiving CMS funding must have antibiotic stewardship program Leadership:(ID trained MD +/- ID Pharmacist) + $ support Expectations: Audit abx use compared to “benchmarks” Data source: EHR for local & National comparisons Example: FQ use by hospital, specialty, DRG & provider. Note: Dr Woodliff (MS ACP): 93 page review w/recs

Concerns: Computer time, defining “value”, need to engage practitioners, ease of gaming Funding consequences from CMS are vague

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

RESISTANCE: NEW THREATS EVERYWHERE GNB – Carbapenemase* & ESBL- prod. GNB (sens-carbapenems)

MRSA – Vancomycin -MIC creep Bacteroides fragilis -Clind, moxi N. gonorrhoeae* -Cefixime, FQ Influenza* –Oseltamivir (2006) M. tuberculosis* -Rif, INH Malaria –Artemisinin *Potential for “untreatable status”

MAJOR RESISTANCE THREATS CDC October, 2013

URGENT *C. difficile *Carbapenem-Resistant GNB

*N. gonorrhoeae

SERIOUS *Acinetobacter *Campylobacter *Candida sp. *ESBL-prod GNB *VRE *P. aeruginosa *Shigella *MRSA *S. pneumoniae *M tuberculosis

Preventing antibiotic-resistant infections, 4,000 US hospitals, CDC, March, 2016 Major resistant bacteria Recent data ESBL Enterobacteraceae 18% Enterococcus- VRE 27% MDR P. aeruginosa 13% MDR Acinetobacter sp 45% Carbepenemase + GNB 3%

WHO Prioritized Resistance List Critical Acinetobacter baumanni Carbapenem-resistant P. aeruginosa Carbapenem resistant Enterobacteraceae Carbapenem-resistant High Enterococcus faecium Vanc/Meth-resistant Staph aureus Vancomycin-resistant H. pylori Clarithromycin-resist Salmonella/Campylobacter FQ-resistant N. gonorrhea FQ; 3d gen ceph-resist Medium S. pneumoniae Pen-resistant Shigella spp Amp or FQ-resistant

EPIDEMIOLOGY OF NDM-1 POSITIVE ENTEROBACTERACEAE

Method: Enterobacteraceae isolates in Reference Labs (UK and India) → carbapenem resistance → Hodge test, etc. → PCR for bla NDM-1 gene

Results: UK-37 strains, India-70 strains Sensitivity 107 Pip-tazo 0 Meropenem 3% Cephalosporins 0 Amikacin 0 Ciprofloxacin 8% Tigecycline 67% Colistin 100%

Colistin & polymyxin dosing* Colistin: 2.5-5.0 mg/kg/d IV q6-12 hr

Renal Failure: GFR 50-80: 5 mg/kg/d in 2 DD

GFR 20-50: 2.5-3.8 mg/kg/d in 2 DD

GFR 5-20: 10: 2.5 mg/kg/d q 24 hr

Polymyxin: 0.75-1.25 mg/kg IV q12 hr

Renal failure: GFR 50-80:2.5 mg/kg day 1, then 1.5 mg/kg/d

GFR 30-50: 2.5 mg/kg day 1, then 1-1.5mg/kg/d

GFR < 30: 2.5 mg/kg day 1, then 1-1.5 mg/kg q 2-3 d

*Caution: May need updating

Candida auris: New fungal pathogen (MMWR;2017;66:514; MMWR 2016:65:1234)

History: Described in 2009 with high mortality & frequent resistance Resistance: Fluconazole-86%; Ampho B-43%; Echinoocandins (Caspofungin)-3% US cases- (5/12/17): 122 (most- S Asia & S Amer) Prevention: Private room, Room decontamination: Na hypochlorite (like C difficile) Other: C glabrada- Resistance echinocandin-8%

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

NUMBER OF NEW ANTIBIOTICS BY YEAR

0

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'83-'87 '88-'92 '93-'97 '98-'02 '03-'07 '08-'12

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‘13-16

Intra-abdominal sepsis:Ceftazidime/ avibactam+Metro Vs. Meropenem (Mazuski JE et al CID;2016:62:1380)

N Ceft/avi+Metro Meropenem N 413 410 Cure 337 (82%) 349 (85%) ADR 42(8%) 36 (7%)

Ceftazidime-Avibactam Sader H Antibicrob Ag Chemother 2014;58:1684 Class: Betalactam-Betalactamace inhibitor (BL-BLI) Recent: More and more BLI resistance, esp KPCs Avibactam- Novel non-betalactam-BLI inhibitor Benefit: Avibactam greatly increases ceftazidime activity vs GNB (4-1024x depending on pathogen) No benefit vs Acinetobacter, Burkholderia, anaerobes FDA approval: 1) Monotherapy for complicated UTIs 2) Intra-abdominal sepsis (with metronidazole) Dose: 2/0.5 gm q8h IV ADRs: GI and infrequent serious skin reactions

Ceftazidime/avibactam de Jong BLM Antimicrob Ag Chemother 2016

In vitro vs 34,062 Enterobacteraceae: % susc. Ceftaz/avibactam- 99.8% Meropenem 97.2% Meropenem resist 83.5% Ceftazidime 75.6% Cefepime 77.3% Pip/tazobactam 84.0%

CEFTAZIDIME-Avibactam: Activity (Sader H AAC 2014;58:1692)

In vitro activity clinical isolates: % sensitive Microbe N Ceft Ceft/Avi Mero All coliforms 640 89% 100% 99% Klebsiella 1,847 100% 99% 94% E.coli 767 92% 100% 99% Morganella 295 86% 100% 100% P. aeruginosa 1,967 83% 97% 82% ESBL + 328 31% 97% 99%

Ceftolozane/Tazobactam Zerbaxa Class; Cephalosporin/Beta-lactamase inhibitor Spectrum: Active verses most enteric GNB Special advantage: Active vs ESBL; some multiply resistant P. aeruginosa Dose: 1.5 gm q 8 hrs infused over 1 hr; Dose modification for renal failure Cost: $240/day; Doripenem-$120; Imipenem- $50; Cefepime- $16; Pip/tazo-$40; Cefotaxime- $10 FDA Approval: Complicated UTIs & intra-abdom infections

Antimicrobials vs. Nosocomial Respiratory tract infection Pathogens Sutherland CA J Thorac Dis 2017;9:2014

Results: N=3,771; P aeruginosa-28%;K. pneumoniae-13% Enterobacter sp.-13% Ceftolozane/ Meropenem 88% tazobactam 95% Tobramycin 87% Colistin 95% Pip/tazo 83% Ertapenem 94% Cefepime 83% Imipenem 92% Ceftazidime 80%

Ceftolozane/Tazobactam to Treat Pneumonia Caused by MDR P. aeruginosa (Vickey SB Pharmacology 2016;36:e154)

Issue: Drug approved for UTIs and IAS, not pulmonary infections due to poor lung penetration. Note: Drug does achieve good penetration into ALF Case: Cystic Fibrosis patient w/pulmonary infection that failed tobra/Cipro; then responded to 10 day course of Ceftolozane/Tazobactam Note: Anecdotal, but reminder of lung limitation of this agent & ? Ceftaz/avibactam- lung infections

Recent FDA Approvals for SSTI • Tedizolid (SIVEXTRO) Class: Oxazolidinone; Administration: IV or PO Activity: MRSA, VRE; Trial: SSTI vs linezolid Advantages: QD ; oral & IV; well tolerated; cost $235/d • Dalbavancin (DALVANCE) Day 1: parenteral 1000 mg parenteral; Day 8 500 mg IV or IM; Spectrum: Vancomycin-like Advantage: T ½=6 days -early hosp discharge; OPD management MRSA etc. Cost $1,788/500mg • Oritavancin (ORBACTIV) One 1,200 mg IV over 3 hrs; Cost- $2,600/dose

Comparative costs for new MRSA agents Drug Regimen Cost Course

Vancomycin 30-60 mg/kg/d IV $3.80/500 mg $ 220 Tedizolid 200 mg po or IV x 6 $235/d $1,410 Linezolid 600 mg IV or po bid $279/d $1,670 Dalbavancin* 1000 mg IV 500 mg day 7 $1788/500 mg $5,364 Oritavancin* 1200 mg IV X1 $2,600/1 dose $2,600- $5,200 * Possible concern for ADRs due to long T1/2

Oritavancin Stewart CL et al Infect Dis Ther 2017 4/6

Review of 1959 patients in Phase 3 trials of Gram pos bacterial infections treated oritavancin vs vancomycin Pathogens: S. aureus (MRSA & MSSA), Strep pyogenes & Enterococcus faecalis. In vitro: MIC90 S. aureus-0.12 mcg/mL; Strep pyogenes-0.06 mcg/mL; E faecalis 0.06 ug/mL Conclusion: Single dose oritavancin is equivalent to 7-10 days of bid vancomycin for soft tissue infections involving the implicated pathogens

Clostridium difficile Infection

Priority: Most common Healthcare-associated infection US annual data (2015): 500,000 cases ; 30,000 deaths and 20% relapse rate; cost $1-4,000,000,000/yr Treatment: Outcome of PO vancomycin vs PO or IV Metronidazole: similar Fidaxomycin: Reduced relapse rate 15% vs 25% (p=0.05) (Louie T et al NEJM 2011;364:422) Issue: Cost/benefit

Fidaxomycin:FDA-approval trial CDI Rx Response Relapse Cost/ Rate Rate course Fidaxomycin 88% 14% $2,800* Vancomycin 87% 26% $ 680 *Cost effective for severe disease & 1st relapse (Nathmic: Abx & Chemother 2015;69:2901)

C. difficile :Bezlotoxumab Trade name: Zinplava (Merck) Mechanism: Monoclonal antibody toxin B Trial: Tested to prevent relapse +/- Anti-toxin A (Actoxumab) that showed no significant activity Results: rate of relapse: N=1554! Benzlo Placebo Rate of relapse MODIFY 1 22% 33% MODIFY 2 19% 33% FDA: Approved for prevention of CDI relapse Cost: $3,800/dose !!!

Clostridium difficile Infection- New drugs & Vaccines

Agent Phase Mechanism Syn-004 II Hydrolyzes beta-lactamases in gut Ridinilazole III Selectively targets only C. difficile ! FDA-Fast track; Phase 3 trial vs fidaxomycin & Vanco Cadazolid II Anti-B; Vs Vanco-Relapse 18% v 50% Non-toxigenic C. difficile strain NTCD-M3 Vaccines: 3 in phase 2/3 trials: Sanofi Pasteur (Phase 3 trial); Pfizer & Valpeva (phase 2 trials)

CDI: Recommendations of 5 international societies: Feher C Infect Dis Ther 2016;5:207 1st episode: Moderate Metronidazole 500 mg tid 10-14 days Severe Vancomycin 125 mg qid 10-14 days Severe & complicated: PO vanco or IV metro or both Relapses First Repeat first treatment Multiple Vanco w/taper or pulse or Fecal transplant or Fidaxomycin 200 mg q 12 h x 10 days

NHS: CDI epidemic throughout the UK

Decrease rate mandate Fired Administrators

Response: 1) Epidemiology: NAP-1 2) “Stopped” FQ (+ cephalosporins) 3) Gene sequencing- Infection control

Result: Rates ↓ 80%!!

CDI: British Health System

HBV GUIDELINES-2017 European Assoc for Study of Liver Disease (J Hepatol, 2017 pili S00168)

Risk: Cirrhosis & Liver cancer Burden: US total: 2.2 mil; mean cost: $59,507/pt Indication for RX: 1) HBV DNA > 2,000 IU/mL 2) ALT increased + moderate histologic changes or cirrhosis + HBV DNA Treatment: TDF (Tenofovir) or TAF (TDF alafenamide- reduced bone and renal toxicity)

TDF vs TAF for e antigen neg HBV* Trial: Randomized, double-blind phase 3 trial Variable TDF TAF Number 141 285 HBV DNA <29 IU/mL 130 (93%) 268 (94%) Decrease bone mineral -1.9% -2.7% (NS) Creatinine Clearence -4.8% -1.8% (NS) * Buti M Lancet Gastro Hepatol 2016;1:196

Tenofovir Alafenamide (Vermlidy) for Chronic Hepatitis B

Burden: 2.2 million patients in US TDF (Tenofovir (TDF) developed for HIV; TAF: Similar activity to TDF vs HIV & HBV, but reduced renal & bone toxicity Vermlidy is TAF tested and FDA-approved for HBV at AWP retail price $1,280 for 30 25 mg tabs (1 month supply); FDA trial TAF vs Vermlidy treatment-48 weeks

HEPATITIS C* No.: US 2.7-3.9 million; globe-250M No. who know it: 40% (NHANES)** Tested and F/U: 22/170 (13%) Risk: Birth 1945-65 >75% with HCV IDU, tx <1992, hemodialysis, abn LFTs Deaths/yr: 15,106 (2007) Exceeds HIV Treatment - SVR (cure): >95% (2014) Cost of FDA-approved drugs: $84-194K AWP cost to treat all HCV pts=total cost all drugs (US), but $ deals by volume CDC: Screen birth cohort and “at risk” *MMWR 2012;61 RR4:1 **NHANES Hepatology 2012;55:1653

OMADAOCYCLINE Pfaller MA AAC 2017; AAC.00018

Class: Aminomethylcycline; Status: Phase 3 testing Spectrum: Tested vs >42,000 clinical isolates from US, Asia & Europe. Active vs most bacteria in nearly all classes including S. aureus, MRSA; anaerobes, Mycoplasma, M. catarrhalis; S. pneumo; Chlamydia, H. flu, most GNB- BLI & ESBL+ GNB; XDR-GNB; VRE Advantage: Activity vs resistant bacteria Concern: Related to Tigecycline-ADR (mortality issue)

New antibiotics in development

* IV Minocycline: Acinetobacter sp, Stenotrophomonas, Bulkholdaria sp * New Polymyxins: non-nephrotoxic • Meropenem/RPX7009: CRE+ GNB- KPC, A. baumanii, P. aeruginosa * Plazomicin: Active vs CRE; Phase 3 CARE HAP/VAP trial- Equal or superior to colistin

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

ANTIBIOTIC RESISTANCE BUNDLE- 9 suggestions • Short course * Smart antibiotic choices-antibiotic control • Procalcitonin to guide when to start & stop • 72 hr “time out”-evaluate cultures, response • Molecular diagnostics- use and interpretation • Gene-sequencing to inform transmission • Automatic stop orders • IV PO switch early & avoid superfluous

coverage and discharge • Use of contemporary guidelines

Bundle:*Chest X-ray within 4 hours * O2 assessment with appropriate Rx

* Assess: CURB-65 * Antibiotics within 4 hours

Evaluation: Bundle started Oct 2012

assessment of 14,962 CAP patients Results: Bundle use reduced mortality

8.8% vs 13.6%; OR 1.52 (P=0.03)

British Thoracic Society: CAP Bundle Lim WS et al Thorax 2015;70:698-700

Septic shock: 2017 Update & Timing of Abx Jaswal DS Ann Intern Med 2017;163:JC10 Sterling SA Crit Care Med 2015; 30;1907)

Jaswal: Sepsis bundle for goal-directed therapy did not reduce 90 day mortality; revisions: Within 1st 3 hrs: 1. Lactate level, 2. Blood cultures before abx, 3. Crystaloid for hypotension 4. Procalcitonin to assess severity & response including source control Sterling- Meta-analysis 11 studies 16,178 patients Results: RR of mortality: >1 hr delay vs < 1 hr delay: RR 1.49 for mortality for each hour delay

Core elements of outpatient antibiotic stewardship (Sanchez GV MMWR 20116:65:1)

Background: 80-90 % of antibiotic scripts (MACRA weight) US: 269 million/yr; ADR requiring ER visit: 143,000/yr Core elements • Record- EHR for OPD prescribing • Stewardship leader (w/support) • Educate: Providers, administrators, patients • Timely available expertise for consults • EHR data mining: provider, diagnosis, service, drug etc Demo: Meeker JAMA 2016;315:562: Required indication for abx; Audit in EPR compared to peers; Abx – 24% reduction in abx

Outpatient antibiotics by state: 2014 (Adams L et al JAMA 2016;176:70)

Conclusion: 30% of OPD antibiotic scripts for URTI in 2014 were unnecessary Major states by rank: Al, Ar, Ky, La, Ms, Te, WV Concerns: Physician, facility grading in MACRA, resistance and cost Note: Antibiotics- only drugs with population harm (Spellberg B et al JAMA2016;315:1229)

Recent Antibiotic guidelines Acute bronchitis* No abx & no microbiology Pharyngitis*: Pos Strep test only: Betalactam Common cold* “No, never” Sinusitis**: “Watchful waiting” x >7 days Asymptomatic UTI *** : No abx due to harm- symptomatic UTI & resistance *ACP 2016; **Am Acad Otolaryngol, 2015: ***IDSA, 2015

Antibiotics for acute sinusitis Caspersen LA; Otolaryng Head Neck Surg 2015;53;161

Evidence: Based on 5 relevant Guidelines, 42 Systematic Reviews & 70 randomized trials Initial treatment: “Watchful waiting” for all patients with uncomplicated acute sinusitis regardless of severity: “Watchful waiting” means no antibiotics for 7 days unless symptoms are worsening or persist for > 7 days. Preferred antibiotic: Amoxicillin +/- clavulanate X 5-10 days Patient information Plain language for consumers

A 18 year old year old college student complains of a severe sore throat. A rapid beta-strep test is negative. The recommended management is:

A. Symptomatic treatment B. Penicillin treatment. C. Symptomatic treatment, but

repeat rapid strep test if symptoms do not improve in 3 days

D. Symptomatic treatment is “right by guidelines” but “may be wrong by science”

Response Counter

Fusobacterium necrophorum & GrC Strep cause pharyngitis-Centor RM,

Ann Int Med. 2015;162:876;New PCR test

FDA warning- Fluoroquinolones FDA- approved: 1987 Indications: CAP, AECB, UTI, IAS, Anthrax, sinusitis WHO- Declared Essential drug Largest selling antibiotic in world; ($0.04/pill) FDA warning 7/28/16: New warning ADRs: Tendonitis, Neuropathy, CNS, (CDI not mentioned !!!) 2017: Use only if no alternative, ie- “last resort abx” Note: Warning is now required in all fluoroquinolones by FDA (Livo, moxi, avelox, norflox, gemi)

SHORT COURSE ABX-Cochrane Reviews

*Single dose inferior for pregnant women

Diagnosis Short** Long No Result

CAP 5 7 1,929 ND CAP 3 8 119 ND HAP 7 10-15 1,705 ND VAP 8 15 197 ND Pyelo 7 14 126 ND AECB <5 >7 3,532 ND UTI 1 dose 7 1,622 INF*

SHORT COURSE ABX-Cochrane Reviews

*Single dose inferior for pregnant women ** Short course always ties or wins

Diagnosis Short** Long No Result

CAP 5 7 1,929 ND CAP 3 8 119 ND HAP 7 10-15 1,705 ND VAP 8 15 197 ND Pyelo 7 14 126 ND AECB <5 >7 3,532 ND UTI 1 dose 7 1,622 INF*

Method: Randomized patients with VAP to 1-3 days vs > 3 days; Results by HR ratio Results: 1-3 days >3 days P value Number 259 1031 Mortality OR-0.82 NS Time to extubation 17.2d 17.7d NS Days of antibiotics 2.0 d 10.0 d P<0.5 Time to discharge 17.1 17.7d NS

Ultra-short-course for VAP Klompas M CID 2017;64:870

#3 ANTIBACTERIAL DECISION-MAKING: ROLE OF PROCALCITONIN

Biology: Marker of bacterial replication Utility: Facilitates decision to start or stop antibacterial agents

Europe: Extensive use; US – minimal Cochrane review: 7 controlled trials, 1,458 patients: 51% decrease in Abx (Tang H. Infection 2009;37:497) POC procalcitonin reported (Kutz A Clin Chem Lab Med 2016;54:577-84

PROCALCITONIN LEVELS FOR ANTIBIOTIC DECISIONS IN RTIs – 14 TRIALS, n=4,221 (Schuetz P. CID 2012;55:651)

Control Procal Method: Cochrane Library review of 14 trials of

Respiratory Tract Infections with 4,667 patients Conclusion: Reduced Abx exposure by 3.5

days/patient without adverse consequences

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

A 65 year old man has CAP with fever, cough w/purulent sputum X 2 days & a RLL infiltrate. The most likely pathogen detected with currently available cultures and molecular tests

A. S. pneumoniae B. Anaerobic bacteria C. “Atypical agent” D. Rhinovirus E. No detectable agent

Response Counter

Method: 2,259 pts, X-ray confirmed CAP Micro: Sputum, bronch, urine ag, CDC-PCRs Results: Any pathogen: 38%* Strep. pneumoniae : 5% Atypicals (all 3): 4% Bacteria : 11% Virus / Rhinovirus: 23% / 9% Conclusion:Despite extensive current tests, no pathogen in 62% cases & viruses dominated

COMMUNITY-ACQUIRED PNEUMONIA Jain S et al, NEJM 2015;373:415*

Microbiology of CAP: Musher D et al CID (in press)

Review of 31 reports of etiology of CAP in US 1917-2015; N=21,315 patients Period reported S. pneumoniae 1910-1940 90% 1965-1980 40% 1990-2010 10%

ANTIBIOTIC SELECTION FOR CAP (Bratzler D, CID 2008;47: Suppl 3; S193) Method: Retrospective analysis 27,330 patients >65 yrs hospitalized with CAP 1998-9. Analysis based on PSI-adjusted mortality correlated with drug class & reported as OR for 30 day mortality vs 3d gen ceph Results Drug PSI ll/lll IV/V P value Fluorquinolone 0.9 0.7 0.001 Ceph/macrolide 0.9 0.7 <0.001 Timing: Significant Mortality with >4 hr abx delay

CDC CAP Review: Leads to draconian changes in current concepts of CAP if correct

High quality studies other countries w/different results; due to pediatric Prevnar-13 vaccine policies- “herd immunity” This is the largest CAP study in US using optimal diagnostics. Apparent conclusions: 1) We don’t know the pathogen in most (60%) of CAP cases even with use of all current diagnostics. 2) We need to accept “viral (rhinovirus etc) pneumonia” 3) We know abx treatment should be started rapidly and old guidelines for abx still apply-maybe

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

A 67 year old woman has C. difficile diarrhea with 2 relapses following PO vancomycin for the first relapse and Fidaxomicin after the second. The treatment with greatest probably of cure now is?

A. PO vancomycin with a tapering dose

B. PO vancomycin followed by probiotics

C. Combination treatment with IV metronidazole and PO vancomycin

D. PO Bezlotoxumab E. Stool transplant

Response Counter

open.biome: Zain Kassam Status: Non-profit to supply stool for transplants Donors: extensively screened for disease and resistant bacteria in colon- 2.8% accepted supply stool 3x/wk; shipped in frozen state 50 states & 7 countries at $485/specimen. Experience (4/1/17) 24,400 specimens for relapsing CDI. Success rate: 87% Plan: 1. Consortium of centers for NIH therapeutic trial for 5 year follow-up obesity, diabetes, metabolic syndrome etc 2. Define the microbial components for FDA-approval as drug 3. Collaboration w/Finch for novel oral capsule that delivers contents to colon for PO use 4. Two controlled trials show efficacy for acute UC

Stool transplant: The future Current status: Well established as preferred treatment for relapsing CDI (after 2d relapse (IDSA 2010 guidelines). Other conditions: (Cohen NA Dig Dis Sci 2017): Pouchitis; Metabolic Syndrome; Hepatitis B; autism; GVH; Sepsis; hepatic encephalopathy; removal of colonic abx-resistant bacteria (23/23 single case reports successful) Controlled clinical trials: Pancreatitis; IBD; Primary sclerosing cholangitis; pancreatitis; removal of abx -resistant bacteria, metabolic syndrome; AIDS

MENU MACRA

Bad Bugs: Resistance

No drugs: Pipeline

Stewardship

CAP

Microbiome

Vaccines

Vaccine Coverage: US, Adults, 2013 CDC National Center for health stastistics

(MMWR 2015;64:95) Vaccine Number Age-yrs % Pneumococcal vaccine 7,433 >64 60% Tetanus within 10 yrs 14,159 >19 17% Zoster 10,160 >60 20% HPV 1 dose Female 2,077 19-26 37% 1 dose Male 1837 19-26 6%

The Next Epidemic- Lessons from Ebola (Bill Gates NEJM 2015;372:1381) YOU’RE NEVER READY FOR THE BIG ONE Issue: Prepare for epidemic that could kill > 10 mil Examples: Flu-1918; HIV1980; SARS Precedent: War – NATO Last example of preparing for pandemic: Dark Winter- Smallpox (Inglesby T CID; 2002 34:972) Recommended components: 1) Health systems; 2)Surveillance; 3)Trained respondants; 4) Good data; 5) Diagnostics, vaccines, drugs

Microbial epidemics that required local ID guidance

Toxic shock-S. aureus Norovirus AIDS C difficile NAP-1 West Nile Virus Measles Lyme disease Anthrax (bioterrorism) H1N1 influenza Iatrogenic fungal meningitis SARS Ebola MERS Food-borne-Listeria, Salmonella S aureus USA-300 Ebola Legionella Zika (and other arborviruses)

Dengue: (“Bone-break”) *US nearly all imported *Sx High fever, HA, joint pains Chikagungunya: “Bent-up” • Sx: Fever, Severe joint pains, 44% disabling joint sx at 1 yr. (Medicine 2012;91:212) Zika virus: Fever, rash, joint pains; S. America (esp Brazil), Pregnancy complication: birth defects-30%;Microcephaly-7% >4,000 cases; GBS- association (STD, persistence) Yellow Fever: Mortality: 3.5-7.5% (vaccine, but shortage) Common Denominator: All transmitted by A. aegypti Control: Mosquito control & vaccines + Anti-mosquito vaccine See: Paules C & Fauci A NEJM 2017;376:1397

Mosquito-borne arborviral infections

Lab-confirmed Zika infections in US (MMWR 2017;66:366-700) Total US cases: 5,247 (5/3/2017) Alabama: 40 Mississippi: 25 Highest in US: NYS-1021; Ca:447; Local-transmission:-Fl-218;Texas-6 Unique features: Persistance-6 mo; STD; Neurotrophic- microcephaly & GBS

New zoster subunit vaccine Lal H et al, NEJM 2015;372:2087

Product: HZ/su Trial: Randomized, placebo-controlled trial, 15,411 participants, age >50 yrs 18 countries, Regimen: 2 IM doses 2 months apart Results at 2 years Vaccine Control Number 7,698 7,713 Zoster 6 210 Efficacy: 97% ADRs 17% 3%

THE END: Points to stress MACRA: Needed based on cost & outcomes, but

Resistance crisis: Must reduce use of antibiotics

Procalcitonin to inform when to start & stop abx

Short course antibiotics always win

Follow guidelines

CDI: Prevention-abx control trumps Infec Control

CAP: Pathogen -??? Treatment is usually empiric

Stool transplant: CDI & ? Multiple other uses

Time to start abx; sepsis-<1 hr; CAP<4 hr

THE END & Good Luck