What s New in Infec4ous Diseases? Azithromycin for Preven4on of Exacerba4ons of COPD 2/20/12. Azithromycin for Management of Chronic Illness

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1 What s New in Infec4ous Diseases? Catherine Liu, M.D. Assistant Professor Division of Infec4ous Diseases University of California, San Francisco Azithromycin for Preven4on of Exacerba4ons of COPD Azithromycin for Management of Chronic Illness Coronary artery disease Several large RCTs fail to show benefit 1 Cys4c fibrosis Improved FEV1, exacerba4ons, weight among those chronically infected with Pseudomonas 2 No change in FEV1, but exacerba4ons, weight among those uninfected with Pseudomonas 3 COPD Several small studies with conflic4ng results 1 O Connor JAMA 2003; Grayston NEJM 2005; Cannon NEJM 2005; 2 Saiman JAMA 2003; 3 Saiman JAMA

2 RCT: Azithromycin 250 mg PO QD vs. placebo x 1 year 17 sites, 1117 pa4ents, Inclusion criteria: >40 years old with COPD and anyone of the following: Con4nuous supplemental O2 Receipt of systemic steroids within past year Prior ER visit or hospitaliza4on for exacerba4on No acute exacerba4on of COPD 4 wks prior to enrollment Albert NEJM 2011; 365: Was azithromycin beder? Propor%on of Par%cipants Free of Acute Exacerba%ons of COPD Rates of acute exacerba%ons of COPD per person- year Median 4me to first AECOPD: 266 vs. 174 days, p <.001 NNT = 2.86 to prevent 1 exacerba4on Albert NEJM 2011 p= Mean decrease in SGRQ scores Hospitaliza4on, any cause Secondary Outcomes Hospitaliza4on related to COPD ED, urgent care visit Unscheduled office visit Intuba4ons Placebo Azithromycin Albert NEJM

3 Adverse Events No mortality difference Adverse event Azithromycin Placebo P- value Hearing decrement 25% 20%.04 Coloniza4on with macrolide resistant organisms 52%=>81% 57%=>41% <.001 Albert NEJM 2011 Considera4ons for clinical prac4ce Primary benefit in decreasing frequency of exacerba4ons and also improved quality of life. Consider use in pa4ents w/ frequent exacerba4ons of COPD despite op4mal therapy. If plan to use, assess for: Baseline QTc interval and concurrent meds that prolong QTc Baseline hearing abnormali4es, monitor over 4me. Unknowns: Safety profile beyond 1 year Long- term impact on bacterial resistance preclude use of azithromycin for subsequent exacerba4ons/ pneumonia? Would less frequent dosing (i.e. three 4mes weekly) produce same benefits with fewer side effects? Beyond MRSA, VRE, and ESBL: The Growing Threat of Carbapenem- Resistant Enterobacteriaceae (CRE) You ve got a superbug. 3

4 Carbapenem- Resistant Enterobacteriaceae (CRE) Enterobacteriaceae are common causes of community and hospital- acquired infec4ons: - E. coli, K. pneumoniae, Citrobacter, Enterobacter, Morganella, Proteus, Providencia, Salmonella, Serra;a - Rise of extended- spectrum β- lactamase (ESBL) E. coli and K. pneumoniae carbapenem use CRE contain a diverse group of carbapenem hydrolyzing β- lactamases Usually mul4- drug resistant: all β- lactams Open resistant to fluoroquinolones and aminoglycosides Limited Rx op4ons: colis4n, maybe 4gecycline Nordmann Emerging Infec4ous Diseases 2011; 17: Worldwide distribu4on of K. pneumoniae carbapenemase (KPC producers) Nordmann EID 2011; 17: June- Dec 2010: 356 cases 42% long- term acute care hospitals 6% skilled nursing facili4es Median age 73 4

5 Worldwide distribu4on of New Delhi metallo- β- lactamase (NDM- 1) Nordmann EID 2011; 17: What s the fuss over NDM- 1? NDM- 1: Causes for concern Unlike others, NDM- 1 gene found not only in a single species but in many unrelated species Gene found on an easily transmissible gene4c element that encodes resistance to other abx. Frequent acquisi4on by K. pneumoniae and E. coli (including a strain known to be a cause of community- acquired infec4ons) Massive reservoir on the Indian subcon4nent (> 1.4 billion people) 5

6 NDM1+ bacteria in: 2/50 tap water 51/171 seepage 0/70 controls (sewage water, Wales) Lancet ID 2011; 11: NDM- 1 + bacteria How well does NDM- 1 transfer to other bacteria? Performed experiments to transfer bla NDM- 1 plasmids from the environmental isolates to: E coli J53, Shigella sonnei, & Salmonella enterica serotype enteri4dis Results: Transfer to E. coli >>> Shigella & Salmonella Most efficient transfer occurred at 30 C > 25 C> 37 C Walsh et al Lancet ID 2011; 11:

7 Walsh et al Lancet ID 2011; 11: Considera4ons for Clinical Prac4ce Consider the possibility of NDM- 1 in pts with carbapenem resistant Enterobacteriaceae (CRE) who have received medical care in India/ Pakistan CRE may be closer to home know your local epidemiology CDC requests that any such isolate be submided for further tes4ng Contact precau4ons are recommended in all pa4ents with CRE Hand hygiene is key to preven4ng the spread of CRE and other MDROs! The An4bio4c Crisis and A Case Study on An4microbial Stewardship 7

8 1995: CDC Campaign for Appropriate An4bio4c Use in the Community 2003: CDC Get Smart: Know When An4bio4cs Work. Targets 5 respiratory infec4ons (> 75% of all office- based abx prescribing for all ages combined): O44s media Sinusi4s Pharyngi4s Bronchi4s Common cold Average annual an4bio4c prescribing rates for ages 14 y (Na4onal Ambulatory Medical Care Survey ) *In , acute respiratory infec4ons s4ll accounted for 58% (but down from 69% in ) of office visits where an4bio4c was prescribed. 8

9 166 pts with acute, uncomplicated sinusi4s in community- based prac4ces: amoxicillin vs. placebo x 10 d No significant difference in symptom improvement at day 3 or at day 10 Slight improvement in symptoms at day 7 favoring amoxicillin but not felt to be clinically significant. No difference in missed work, recurrence, sa4sfac4on with treatment Garbud et al JAMA 2012; 307: An4microbial Stewardship in Management of Hospitalized Pa4ents with SSTI: A Case Study PART 1: Retrospec4ve cohort of 322 pa4ents hospitalized with skin and sop 4ssue infec4ons (SSTI) in 2007 Celluli4s (20%) Abscess (32%) SSTI with complica4ng factor (48%): recent hospitaliza4on or LTCF resident deep 4ssue infec4on, severe celluli4s requiring debridement or fascial biopsy diabe4c or other chronic ulcer human or animal bite bacteremia ICU admit necro4zing fascii4s peripheral arterial disease periorbital or perirectal infec4on Jenkins CID 2010; 51: Microbiology 3% 19% 13% 3% 40% 65% 43% MRSA 19% MSSA 97% S. aureus or Streptococcus 74% S. aureus or Streptococcus ONLY S. aureus Streptococci Enterococci Gram nega4ve Anaerobes Other Jenkins CID 2010; 51:

10 An4microbial Usage 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% * Gram An4- MRSA posi4ve only *p<.05 * Gram nega4ve Anaerobic Celluli4s Cutaneous abscess Complicated SSTI Jenkins CID 2010; 51: Other Diagnos4c Studies 80% 70% 60% 50% 40% 30% 20% 10% 0% Celluli4s Cutaneous abscess Complicated SSTI ESR or CRP Plain film Ultrasound CT or MRI Diagnos4c yield plain film (1%), U/S (0.3%), CT (2%), MR (1%) Jenkins CID 2010; 51: Summary of Findings S. aureus and streptococci were the dominant pathogens Broad- spectrum gram nega4ve and anaerobic agent use very common Median dura4on of therapy: days ESR/ CRP and imaging studies open used; lader with low diagnos4c yield Jenkins CID 2010; 51:

11 PART 2: Implementa4on of a clinical prac4ce guideline for inpa4ent celluli4s and abscess July : Empiric Rx: IV vancomycin, then tailor to culture, step- down to PO therapy for 5-7 days Specifically discouraged: Gram nega4ve and an4- anaerobic agents ESR CRP Plain films, CT, MRI Developed electronic admission order set Educa4onal campaign for faculty and housestaff peer champions from 5 departments (ER, adult urgent care, internal medicine, general surgery, orthopedic surgery) Audit/ feedback Jenkins Arch Intern Med 2011; 171: An4bio4c U4liza4on Post- Interven4on 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% * * * * Vancomycin Gram nega4ve An4- pseudomonal An4- anaerobic Baseline Interven4on *p<.05 Jenkins Arch Intern Med 2011; 171: Other Outcomes Diagnos4c studies: use of CRP, similar use of ESR in use of CT/ MRI U4liza4on of consulta4ve services: in general surgery and ID consults Median dura4on of Rx (13 vs. 10d, p<.001) pa4ents treated for < 10d (14% vs. 38%, p <.001) pa4ents treated for > 14d (33% vs. 12%, p <.001) Clinical failure (7.7% vs. 7.4%, p=ns). Also no difference in: Recurrence, rehospitaliza4on due to SSTI, length of hospital stay Jenkins Arch Intern Med 2011; 171:

12 Considera4ons for Clinical Prac4ce In most hospitalized pa4ents with SSTI: Use of broad spectrum an4bio4cs with gram nega4ve and anaerobic ac4vity is unnecessary Shorter dura4ons of therapy (7 days) likely adequate Role of addi4onal diagnos4cs may be limited to selected cases and needs to be further defined ESR/ CRP Imaging (plain film, U/S, CT, MRI) Clinical guidelines pathway helpful for implementa4on Requires physician champions for success Measles: The Resurgence of a Vaccine- Preventable Disease Measles in the U.S. in was a record year for measles in the U.S. January 1- July 8, 2011: Measles incidence 1.8X higher than the average incidence % unvaccinated or unknown vaccina4on status Most cases imported from measles endemic countries or outbreaks abroad. Unvaccinated U.S. travelers abroad Unvaccinated visitors to U.S. Secondary cases linked to imported cases McLean IDSA Oct 2011 abstract #LB

13 Characteris4cs of measles cases 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Age Distribu%on of Measles Cases < 12 mo 1-4 yr 5-19 yr 20 yr Age- Specific Incidence (cases/ million) 6-11 mo mo 16 mo- 4 yr Measles in Europe, 2011 Outbreaks in 36/ 53 countries: > 26,000 cases, 7,288 hospitaliza4ons, 9 deaths > 14,000 cases in France Median age 15 years: 15 y (49.4% of cases) 5-14 y(24.7%) <5 y (25%) 90% not vaccinated or unknown status WHO report, December 2, 2011 Measles Outbreak, Indiana June- July 2011 Index case: 24 y unvaccinated US resident Developed a rash on return flight from Indonesia Admided to hospital, suspected to have dengue fever Measles diagnosis not considered un4l 2 weeks later when 5 family members presented with sx 14 secondary cases Median age 11.5 (15 mo- 27 yr) 13 unvaccinated (One 23 mth received 1 dose MMR) 1 pregnant woman hospitalized for acute pneumoni4s MMWR Sept 2, 2011/ 60(34):

14 Clinical features Highly infec4ous, up to 90% of suscep4ble persons develop measles following exposure to droplet nuclei. Can live on infected surfaces for up to 2 hours Signs and symptoms: Fever Rash starts on face/ hairline and spreads downwards 3 C s: cough, coryza, conjunc4vi4s. Koplik s spots Complica4ons: pneumonia, ear infec4ons, diarrhea, encephali4s, subacute sclerosing panencephali4s 14

15 The MMR Vaccine Controversy 1998: Andrew Wakefield publishes paper in The Lancet sugges4ng poten4al link between MMR vaccine and au4sm Well, the interes4ng thing is that the damage, the behavioural or developmental change tends to occur quite soon aper administra4on, and this is where, why parents or GPs or paediatricians have been able to make the link, the associa4on with MMR. Mul4ple subsequent studies published showing no link between MMR vaccine and au4sm 2010: Ar4cle retracted by The Lancet due to financial and scien4fic conflicts of interest, data manipula4on, and ethical concerns Considera4ons for Clinical Prac4ce Consider measles in returning traveler with fever and rash Measles is highly infec4ous take infec4on control precau4ons to prevent transmission. Outpa4ents: Place a mask on pa4ent Hospitalized pa4ents: Place in airborne precau4ons. Encourage immuniza4on of your pa4ents and their children! 15

16 A Shorter, Simpler Op4on for Treatment of Latent Tuberculosis? Background: Latent Tuberculosis 5-10% of infected individuals develop ac4ve TB with greatest risk occurring within the first 2 years INH is the current standard Rx for LTBI with efficacy of 69-93% for preven4on of TB. Long treatment dura4on pose problems with compliance. Prospec4ve, open- label, randomized trial: INH x 9 mths (self- administered) vs. INH + rifapen4ne 900 mg once weekly x 3 mths (direct observa4on) Enrolled 8053 pts btw U.S., Canada, Brazil, Spain High risk pts (71% close contact, 25% recent conversion) Follow- up: 33 months 16

17 Cumula4ve rate of TB Treatment comple4on Discon4nua4on due to AE Results INH alone INH + rifapen%ne p- value Within noninferiority margin of 0.75% 69% 82.1% < % 4.9%.009 Any serious AE 2.9% 1.6% <.001 Hepatotoxicity 2.7% 0.4% <.001 Possible hypersensi4vity 0.5% 3.8% <.001 CDC Recommenda4ons Dec 9, 2011 Weekly INH + rifapen4ne x 3 mths under DOT is recommended as an equal alterna4ve to INH x 9 months in pts 12 years with: High quality evidence Recent contact with ac4ve case Conversion from nega4ve to posi4ve PPD or QFT + PPD/ QFT and radiographic findings of healed pulmonary TB Expert Opinion/ Lower Quality Evidence Situa4ons where pt unlikely to complete 9 mths INH Correc4onal se}ngs, clinics for recent immigrants, homeless shelters Not recommended: HIV pts on an4retrovirals, pregnant women CDC Recommenda4ons (cont d) Daily observed therapy (DOT) recommended as missed doses or altered dosing intervals/ amounts may jeopardize safety or efficacy. Close monitoring for adverse effects is recommended. Serious AEs with INH and RIF- PZA (fatal hepatotoxicity) only came to aden4on aper regimens widely adopted). ATS, CDC, IDSA revising joint guidelines for LTBI 17

18 2/20/12 Advances in Influenza Vaccine Development Current egg- based vaccines: Lengthy produc4on period limits capacity to match vaccine to circula4ng strains Suscep4ble to microbial contamina4on Difficul4es with growth of certain subtypes vaccine shortages Hemagglu4nin may be altered when grown in chick embryos. Cell- culture derived vaccines: Shorter vaccine produc4on 4me allows more 4me to decide which strains to include in the vaccine, available on short no4ce during any season Maintained in asep4c environment Viral growth not an issue Preserves structure of the an4body- combining sites on the hemagglu4nin thus preven4ng altera4on in an4genicity Safe in persons with egg allergy Lancet 2011; 377: Wright NEJM 2008;358:24 18

19 Phase III trial 7250 healthy adults (18-45 yo) randomized to Vero cell- culture vaccine vs. placebo during flu season. Overall protec4ve efficacy of 79% consistent with data from egg- derived vaccines. Higher rates of local reac4ons and increased rate of fever, myalgias, arthralgia, chills, but no significant difference in serious adverse effects Lancet 2011; 377: On the Horizon: A Universal Flu Vaccine? Current vaccines target the globular head of hemagglu4nin (HA) mutates every season Stem domain of HA: highly conserved region of the virus In 2009, human monoclonal an4body (CR6261) iden4fied that broadly neutralizes group 1 influenza A viruses (H1, H5, H9, H2) by targe4ng conserved epitope in stem domain. Wang Science 2011; 333: Iden4fied a human monoclonal an4body CR8020 found to have broad neutralizing ac4vity against group 2 influenza A viruses (H3, H7) In mice challenged with H3N2 or H7N7: Prophylaxis effec4ve Therapy when given within 2 days aper H3N2 challenge and within 3 days aper H7N7 challenge prevented mortality. CR8020 Highly conserved across 16 group 2 influenza A 11/15 residues are 99% conserved 4/ 15 residues conserved in 56-81% (did not adversely affect binding) CR6261 Shared residues Wang Science 2011; 333:

20 Summary & Considera4ons for Clinical Prac4ce Cell- culture derived vaccines are safe and effec4ve and may become available in the near future In the longer term, 2 monoclonal an4bodies CR6261 and CR8020 create possibility of a universal influenza A vaccine: Broad immunity to range of influenza viruses Perhaps no need to develop a yearly vaccine and do away with the annual flu shot? 20