2013 Antimicrobial Update - PowerPoint Presentation

Slide1

2013 Antimicrobial UpdateOklahoma ACP Chapter October 18, 2013

Michelle R. Salvaggio MD FACP

Associate Professor, Medicine

Section of Infectious Diseases

OUHSC

Slide2

Outline

Clostridium

difficile

Methicillin resistant

Staphylococcus

aureus

Hepatitis C

HIV

I will be discussing off-label use of some medications.

Slide3

Question 1

A 66

yo

WM was recently admitted to the hospital for pneumonia. While admitted he was also diagnosed with

C

difficile

diarrhea and has now completed a course of

metronidazole

. He is calling your office complaining of continued diarrhea. What do you do?

Tell him take a

probiotic

and

Immodium

.

Have him come to the office and submit stool for testing.

Retreat with an extended course of

metronidazole

.

Ask him if he has money saved, if he says yes, prescribe oral

vancomycin

.

Call your GI colleague and arrange for fecal transplantation.

Slide4

C. difficile background

Gram-positive, anaerobic, spore-forming bacillus (“Difficile” because it is difficult to culture)Accounts for 20-30% cases of antibiotic-Major cause of hospital infection, morbidity and mortality.Present epidemic strain (BI/NAP1/027)first reported in the US in 2005Now reported from 40 US states and all Canadian providencesComprises 36% of all C difficile infection (CDI) associated Rates continue to increase in North America

Gerding

D Infect Control Hosp

Epidemiol

2010; 31(S1):S32-S34

Slide5

Slide6

CDI Clinical manifestations

Range from symptomless carriage to fatal pseudomembranous colitis 96% have received antibiotics within the previous 14 days Fever, abdominal cramps, peripheral leukocytosis, and hypoalbuminemia WBC can exceed 30,000-50,000 cells/mL and be indicative of severity

Kelly

CP and JT

LaMont

.

NEJM 2008; 359: 1932-1940.

Slide7

CDI Treatment

Clinical definitionSupportive Clinical DataRecommended TreatmentInitial episode, mild/moderateWBC ≤ 15K, Cr ≤ 1.5 x premorbidMetronidazole 500mg po tid, 10 – 14 daysInitial episode, severeWBC ≥15K, Cr ≥1.5 x premorbidVancomycin 125 mg po qid, 10 – 14 daysInitial episode, severe, complicatedHypotension/shock,ileus, megacolonVancomycin 500mg po/ngt qid + metronidazole 500mg iv q 8 hrs, consider pr vancomycin w ileus1st recurrenceSymptom drivenSame as initial episode2nd recurrenceSymptom drivenTaper or pulse vancomycin

Adapted from Cohen et al. ICHE 2010; 31: 431-455 and Kelly CP. NEJM 2008; 359: 1932-1940.

Slide8

Fidaxomicin (Dificid)

FDA approved in 2011: treatment of Clostridium difficile associated diarrheaGranted New Technology Add On-Payment by CMS (August 2012)Mechanism of actionBacteriocidal against C. dificile in vitro, inhibiting RNA synthesis by RNA polymerases Macrolide but does not confer cross-resistance Low rate of spontaneous resistance (although specific mutation Val-II43-Gly has been identified)

Dificid

Package Insert: http

://www.dificid.com/sites/default/files/prescribing.pdf

Slide9

Fidaxomicin facts

Dose is 200mg po twice daily x 10 daysRetail cost: $4000/course (cash)Very little systemic absorption, essentially no dose adjustment with various other medications, no adjustment with renal or hepatic impairmentWarnings: hypersensitivity reaction (dyspnea, rash, pruritis, angioedema of mouth, throat, face), may report previous allergy to macrolidesAdverse events/side effects: same rate of blood dyscrasias, GI symptoms (N/V/abd pain/GI bleed) as vancomycin

Dificid

Package Insert: http

://www.dificid.com/sites/default/files/prescribing.pdf

Slide10

Fidaxomicin data

Two randomized, double-blinded controlled studies Non-inferiority design Fidaxomicin 200mg po BID vs vancomycin 125 mg po qid x 10 days in patients with CDAD

Dificid

Package Insert: http

://www.dificid.com/sites/default/files/prescribing.pdf

Slide11

Other CDAD Treatment Options

Rifaximin - 400 mg BID for 14 daysNitazoxanide - 500mg BID for 7 – 10 daysFecal transplant - successful in uncontrolled seriesMonoclonal antibodies - against toxins A&BNontoxigenic C difficile

1. Kelly CP and JT

LaMont

.

NEJM 2008; 359: 1932-1940

.

2. Cohen

et al. ICHE 2010; 31: 431-455

.

Slide12

Question 2

In mid January, a 54

yo

woman presents to the hospital with increasing shortness of breath, productive cough and fever. She was diagnosed with influenza 1 month prior and treated with

oseltamivir

. Her chest

Xray

is consistent with lobar pneumonia. Sputum is positive for gram positive

cocci

in pairs. What is the best course of action at this time?

Give her another course of

oseltamivir

Prescribe

linezolid

and send her home.

Do a chest CT with angiography to assess for PE.

Admit her, start

vancomycin

, pip/

tazo

and

cipro

.

You lost me at gram positive

cocci

…

Slide13

Ceftaroline (teflaro)

FDA approved 2010: treatment of acute bacterial skin and skin structure infectionscommunity acquired bacterial pneumonia Mechanism action: cephalosporin (β-lactam) prodrugbacteriocidal against S aureus due to affinity for PBP2a bacteriocidal against S pneumoniae due to affinity to PBP2x

Teflaro

Package Insert: http

://www.frx.com/pi/teflaro_pi.pdf

Slide14

Ceftaroline dosing

Dosing: 600mg IV every 12 hours to be infused over one hour Dosing in renal impairment:CrCl > 50ml/min no adjustmentCrCl >30 to ≤ 50 ml/min 400mg IV every 12 hoursCrCl ≥15 to ≤ 30ml/min 300mg IV every 12 hoursESRD including HD 200mg IV every 12 hoursCeftaroline is dialyzable and should be given after HDNo dosing adjustment with hepatic disease

Teflaro

Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

Slide15

CEFtaroline warnings

Hypersensitivity reactions: to ceftaroline and to other β-lactams CephalosporinsPencillinscarbapenemsC difficile associated diarrheaDirect Coombs’s test seroconversionMonitor for drug induced hemolytic anemia

Teflaro

Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

Slide16

Ceftarolinespectrum of activity

Gram positive: S aureus (MRSA, MSSA), Streptococcus speciesGram negative: E coli, Klebsiella species, H influenzae (possibly Citrobacter, Enterobacter, Proteus)DOES NOT COVER Enterococcus (including VRE)AnaerobesPseudomonas speciesAny ESBL, KPC, etc

Teflaro

Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

Slide17

Ceftaroline data – Acute Bacterial Skin and Skin Structure Infections

Lesion size ≥ 75 cm2Major abscess with ≥ 5cm surrounding erythemaWound infectionDeep/extensive cellulitis

Teflaro

Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

Slide18

Ceftaroline Data- Community Acquired Bacterial Pneumonia

2 studies comparing ceftriaxone to

ceftaroline1 study allowed macrolide on first day, the other did notNo MRSA allowed

Teflaro

Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

Slide19

Question 3

A 62

yo

WF presents to your clinic complaining of fatigue. She asks you test her for everything. You order

TSH, B12,

cbc

,

sed

rate

Vit

D

HIV,

Hep

C

Nothing. She needs reassurance alone.

Referral to therapist.

Slide20

Screening for Hepatitis C: Recommendations

CDC Issued on May 18, 2012USPSTF issued on June 25, 2013Routine HCV screening for all adults born from 1945 through 1965 (currently aged 48 – 68).Numbers of diagnosed patients expected to double, possibly triple

http

://

www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm

http

://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htm

Slide21

Screening: Identifying Estimated 170 Million Persons With HCV Infection Worldwide

World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C: Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16.

Europe

8.9 million

(1.03%)

Americas

13.1 million

(1.7%)

Africa

31.9 million

(5.3%)

Western Pacific

62.2 million

(3.9%)

Eastern Mediterranean

21.3 million

(4.6%)

Southeast Asia

32.3 million

(2.15%)

Slide22

HCV Overview/epidemiology

“Silent Epidemic” - Approximately 3.9 million in the US170 million globallyHIV—1 million USMajority of patients in US have Genotype 1 (75%), few G2 and G3G2—10-15%; EuropeG3—4-6%; AustraliaG4—Middle East, AfricaG5—South AfricaG6—Hong Kong

Predominant cause of chronic liver disease, HCC, and death in US; leading indication for liver transplant TransmissionBloodSexual contactMother-to-child Six genotypesResponse to treatment dependent on genotype

Ghany

MG et al. 2006.

Hepatology

49: 1335-1374.

Slide23

Clinical Manifestations of Hepatitis C

Slide24

Telaprevir (Incivek)Boceprevir (victrelis)

FDA Approved 2011: treatment of Hepatitis C genotype 1 in adults with compensated liver disease including cirrhosisMay be used in treatment naïve, those who have previously been treated with an interferon-based therapy including prior null responders, partial responders and relapsersonly in combination with peginterferon and ribavirinMechanism of actionNS3/4A protease inhibitor

Incivek

Package Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf

Victrelis

Package

Insert:http

://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Slide25

dosing

Telaprevir

DoseStandard—750mg orally every 8 hours weeks 1-12, with food, not low fatResponse and prior response dictate course of peg-interferon and ribavirin (12 to 36 more weeks)Hepatic impairmentNo dose adjustment for mild impairment, Child-Pugh A (score 5-6)Renal impairmentNo dose adjustment for CrCl > 50 ml/min

BOceprevir

DoseWeek 1 -4 peginterferon and ribavirin then add boceprevir 800mg orally every 8 hours with meal or snackResponse, prior response and disease stage dictate course of all 3 meds(total of 28 – 52 weeks)Hepatic impairmentNo dose adjustment for mild, moderate or severe impairment Renal ImpairmentNo dose adjustment for renal impairment

Peg-interferon has only been studied in adults with CrCl > 50ml/min and is approved for use in compensated cirrhosis only

Incivek

Package Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf

Victrelis

Package

Insert:http

://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Slide26

WARNings

Telaprevir

Adverse EffectsBlack box: rash (Stevens Johnson, DRESS, TEN)Anemia GI: nausea, vomiting, diarrhea, anorectal discomfort, dysgeusiaCost (30-day supply)Standard dose $18,350With peg-interferon + ribavirin = $21,000

Boceprevir

Adverse EffectsAnemiaNeutropeniaDysgeusiaCost (30 day supply)Standard dose $4,600With peg-interferon + ribavirin = $7000

Incivek

Package Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf

Victrelis

Package

Insert:http

://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Slide27

Telaprevir and Boceprevir drug interactions

Antiarrythmics: lidocaine, flecainide, amiodarone, digoxinAntibacterials: clarithromycinAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenytoinAntidepressants: escitalopram, trazodoneAntifungals: itraconazole, posaconazole, voriconazoleAntigout: colchicineAntimycobacterial: rifabutinBenzodiazepines: alprazolam, IV midazolam, zolpidemCalcium channel blockers: amlodipine, all othersCorticosteroids: prednisone, nasal fluticasone/butesanideHMG co-reductase inhibitors: atorvastatin, all othersHormonal contraceptives: ethinyl estradiol

Incivek

Package Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf

Victrelis

Package

Insert:http

://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Slide28

SVR Rates With BOC or TVR in Genotype 1 Treatment-Naive Patients

0

20

40

60

80

100

SVR (%)

PegIFN/RBV

BOC or TVR + PegIFN/RBV

38-44

63-75

Poordad F, et al.

N Engl J Med. 2011;364:1195-1206.

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Slide29

SVR Rates With BOC or TVR in GT1 Treatment-Experienced Patients

0

20

40

60

80

100

SVR (%)

Relapsers

Partial Responders

69-83

PegIFN + RBV

Bacon BR, et al.

N Engl J Med. 2011;364:1207-1217

. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

Vierling JM, et al. AASLD 2011. Abstract 931.

Null

Responders

BOC or TVR + PegIFN + RBV

24-29

40-59

7-15

29-38

5

Slide30

Hepatitis C Treatment Options

First-line therapy

Genotype 1

Telaprevir or Boceprevir + Pegylated interferon/Ribavirin

Genotypes 2/3

Pegylated interferon/Ribavirin

Treatment Duration

Response-guided therapy

Not to be used in cirrhotic and/or null responders

Determined by early virologic decline

RVR—undetectable HCV RNA at week 4

eRVR—undetectable HCV RNA at weeks 4 and 12

Slide31

Question 4

A 28

yo

man presents to your office. He states he has heard about a medicine that will keep him from getting HIV. He would like for you to prescribe that to him. You

Refer him to Infectious Diseases.

Ask him why he thinks he is going to be infected with HIV.

Ask him if he is infected with HIV.

Give him

a package of condoms.

Slide32

US National HIV strategy released July 2010

http://www.whitehouse.gov/files/documents/nhas-implementation.pdf

Slide33

July 16, 2012

FDA approves first drug for reducing the risk of sexually acquired HIV infectionTruvada™ is indicated in combination with safer sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults at high risk. Originally approved 2004 for use in combination with other antiretrovirals for the treatment of HIV-1 in adults and children > 12 years.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm

Slide34

emtricitabine/tenofovir disoproxil fumarate (Truvada) facts

Combination product of two different nucleoside analogs emtricitabine (200mg) and tenofovir (300mg)Given orally once daily (regardless of indication)Retail cost: $1500/monthDosing in renal impairment:CrCl ≥ 50ml/min no adjustmentCrCl 30 – 49 one tablet every 48 hoursCrCl < 30 should not be used (includes HD pts)

Truvada

Package Insert: https

://www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

Slide35

FTC/TDF Black Box warnings

Lactic acidosis and severe hepatomegaly (including fatal cases)Severe exacerbations of hepatitis B have been reported in pts coinfected with hep B and HIV who discontinued FTC/TDFTRUVADA used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and periodically (at least every 3 months) during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for a PrEP indication following undetected acute HIV-1 infection. Do not initiate TRUVADA for a PrEP indication if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed.

Truvada

Package Insert: https://www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

Slide36

Acute antiretroviral syndrome

Vanhems

P, et al. 2002. JAIDS 31: 318- 321.

Slide37

FTC/TDF adverse events/warnings

New onset or worsening renal impairmentFanconi syndromeAvoid concurrent nephrotoxic agentsDecreased in bone mineral densityRedistribution/accumulation of body fatSide effects in HIV positive patients (in combination with other agents): diarrhea, nausea, rashSide effects in HIV-negative patients: no significant difference from placebo

Truvada

Package Insert: https://www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

Slide38

FTC/TDF nPrep data

iPrEx

2499 MSM

International

FTD/TDF v placebo

TDF2

1216

HTXL

men/women in Botswana

FTC/TDF v

placebo

FEM-

PrEP

2056

HTXL women in Kenya, Tanzania, S Africa

FTC/TDF v placebo

Partner’s

1458 HTXL

couples

in Kenya

, Uganda

FTC/TDF v TDF v

placebo

VOICE

2029

HTXL women in S Africa, Uganda, Zimbabwe

FTC/TDF v TDF v placebo

TDF gel v placebo gel

Reduction

in incidence of HIV infection

44% (CL 15 – 63, p= 0.005)

Max 2.8 years

Decreased

rate of infection by 62.2% (study stopped early due to poor retention)

Max 3.7 years

No reduction in infection

Reduction in infection 75% FTCTDF (CI 55-87, p <0.001), 67% TDF (CI 44-81, p <0.001)

TDF

oral and gel stopped early due 6% infection rate for both

No reduction of infection with FTC/TDF

Slide39

Before

MSMHeterosexualDocument negative HIV antibody test immediately before stating PrEPTest for acute HIV infection if patient has symptoms consistent with acute HIV infection+ – if the person reports unprotected sex with an HIV-positive person in the preceding monthDetermine if women are planning to become pregnant or are currently pregnant or breastfeedingConfirm that patient is at ongoing, very high risk for acquiring HIV infectionConfirm that calculated Cockcroft-Gault is >60 mL/min

Truvada

REMS:

http

://

www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients

andProviders

/UCM312304.pdf

Slide40

MSMHeterosexualIf any sexual partner is known to be HIV-infected, determine whether receiving ART; assist with linkage to care if not in care or not receiving ARTScreen for Hep B, vaccinate if susceptible, treat if active regardless of PrEPScreen and treat as needed for STIsDisclose to women that safety for infants exposed during pregnancy is not fully assessed, but no harm has been reportedDo not prescribe to women who are breastfeeding

Before

Truvada

REMS:

http

://

www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients

andProviders

/UCM312304.pdf

Slide41

MSMHeterosexual1 tablet TDF/FTC daily90 day supply renewable after HIV repeat testingFor women confirm pregnancy test is negative or if pregnant informed about use of medication during pregnancyFor active Hep B consider using TDF/FTC for treatmentProvide risk-reduction and PrEP medication adherence counseling and condoms

Beginning

Truvada

REMS:

http

://

www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients

andProviders

/UCM312304.pdf

Slide42

MSMHeterosexualEvery 2-3 months perform HIV antibody test (or antibody/antigen test); document negative resultsAt each f/u for women conduct pregnancy test, document, if pregnant discuss the continued use of PrEP and prenatal-careEvaluate and support PrEP medication adherence at each follow-up visit, more often if inconsistent adherence is identifiesEvery 2-3 months assess risk behaviors and provide risk-reduction counseling and condoms. assess STI symptoms and if present treat Every 6 months test for bacterial STI even if patient is asymptomatic and treat as needed3 months after initiation, then yearly while on PrEP medication, check BUN and SCr3 months after initiation, then every 6 months while on PrEP medication, check SCR and calculate CrCl

Follow-up

Truvada

REMS:

http

://

www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients

andProviders

/UCM312304.pdf

Slide43

MSMHeterosexualPerform HIV test to confirm whether HIV infection has occurredIf HIV positive, order and document results of resistance testing and establish linkage to HIV careIf HIV negative, establish linkage to risk-reduction support services as indicatedIf active hepatitis B is diagnosed at initiation of PrEP consider appropriate medication for continued treatment of hepatitis BIf pregnant, inform prenatal-care provider of TDF/FTC use in early pregnancy and coordinate care to maintain HIV prevention during pregnancy and breastfeeding

Discontinuing

Truvada

REMS:

http

://

www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients

andProviders

/UCM312304.pdf

Slide44

Question 1

A 66

yo

WM was recently admitted to the hospital for pneumonia. While admitted he was also diagnosed

with C

difficile

diarrhea and has now completed a course of

metronidazole

. He is calling your office complaining of continued diarrhea. What do you do?

Tell him take a

probiotic

and

Immodium

.

Have him come to the office and submit stool for testing.

Retreat with an extended course of

metronidazole

.

Ask him if he has money saved, if he says yes, prescribe

fidaxomicin

.

Call your GI colleague and arrange for fecal transplantation.

Slide45

Question 2

In mid January, a 54

yo

woman presents to hospital with increasing shortness of breath, productive cough and fever. She was diagnosed with influenza 1 month prior and treated with

oseltamivir

. Her chest

Xray

is consistent with lobar pneumonia. Sputum is positive for gram positive

cocci

in pairs.

She takes

paroxetine

daily.

What is the best course of action at this time?

Give her a another course of

oseltamivir

Prescribe

linezolid

and send her home.

Do a chest CT to

assess for

empyema

.

Admit her, start

vancomycin

, pip/

tazo

and

cipro

.

Admit her, start

ceftaroline

.

Slide46

Question 3

A 62

yo

WF presents to your clinic complaining of fatigue. She asks you test her for everything. You order

TSH, B12,

cbc

,

sed

rate

Vit

D

HIV,

Hep

C

Nothing. She needs reassurance alone.

Referral to therapist.

Slide47

Question 3b

You test the patient from the previous question for Hepatitis C. Her

Hep

C

IgG

is positive, viral load is 600,000 and her genotype is 1a. Her US shows mild cirrhosis and her LFTs are 1.5 ULN. What is the next step in her management?

Test for HIV, Hepatitis A and B and syphilis.

Have her come back in 6 months and repeat testing.

Schedule her for a liver biopsy.

Refer her to ANYONE treating Hepatitis C.

Start her on

telaprevir

with peg-interferon and

ribivirin

.

Slide48

Question 4

A 28

yo

man presents to your office. He states he has heard about a medicine that will keep him from getting HIV. He would like for you to prescribe that to him. You

Refer him to Infectious Diseases.

Ask him why he thinks he is going to be infected with HIV.

Ask him if he is infected with HIV.

Give him a package of condoms.

Prescribe FTC/TDF.

Slide49

Summary

C

difficile

remains a serious health issue.

Vancomycin

and metronidazole remain the mainstays of therapy.

Fidaxomicin

(

Dificid

) is another treatment option.

MRSA skin and lung infections remain a serious health issues.

Ceftaroline

(

Teflaro

) has been approved for SSTI and may be used in pneumonia.

Ceftaroline

=

cefazolin

+ MRSA coverage

Screen everyone for Hepatitis C.

If

ab

positive, get viral load and genotype

then send

to specialist.

Screen everyone for HIV. Encourage safe sex practices to all of your patients.

If pre-exposure prophylaxis questions come up, send the patient to us.