Emerging ID issues: - PowerPoint Presentation

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Emerging ID issues:Drug Resistant Bacteria & Spreading Viruses

Paul S. Sehdev, MD, MS, FACP, FIDSA

Infectious Disease Consultants &

The Traveler’s Clinic

Providence St. Vincent’s Hospital

October 14, 2011Slide2

Trends in S. aureus Disease

Emergence of MRSA

Emergence of VISA

Emergence of VRSA

Emergence of hVRSA

Community acquired MRSA

Resistance to new agents

Linezolid

DaptomycinSlide3

Emergence of Methicillin Resistance

1961: Methicillin introduced

1962: MRSA identified

1980: 5-10% hospital isolates MRSA

1991: 25% hospital isolates MRSA

2003: 64% isolates in NNISS

Chambers. Emerg Inf Dis;7:178Slide4

Methicillin Resistance: Mechanism

MecA

gene

Encodes a low affinity PBP (PBP2a)

Affects all

-lactam drugs5 types

Variable patterns of drug susceptibilities

Acquired from unknown locus

Mobile transposon-like element

Resistance profiles continue to changeSlide5

http://phsnet.phsor.org/laboratory/micro/antibiotics/QTR%204%202008PSVMCMRSA.pdfSlide6

What is an Extended-Spectrum 

-Lactamase (ESBL)?

Variant of standard TEM & SHV



-lactamases

Result of point mutations Mutated -lactamase has extended spectrum

Degrades 3

rd

generation cephalosporins

Transmitted via plasmids

Over 150 ESBLs identified to date

E.Coli

& K.pneumoniae

Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S.Slide7

Molecular Basis of ESBLs

Amino Acid Position

Enzyme

CTZ MIC

102

162

237

TEM-1

<0.12

Glu

Arg

Glu

TEM-12

4-32

Glu

SerGluTEM-1064GluSerLysTEM-26>256LysSerGlu

Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S.Slide8

ESBLs Detection Methods: Inhibition by Clavulanic AcidSlide9

Inoculum Effect in K. pneumoniae Isolates Containing ESBLs

Antibiotic

MIC

90

(

g/mL)

10

5

CFU/mL

% Susceptible

10

7

CFU/mL

% Susceptible

Meropenem

0.061004100Cefotetan110016

90

Ceftazidime

1,024

11

>1,0245Cefotaxime3267>1,0245Ceftriaxone6456>1,0240Cefepime1689>1280Pip/Tazo1,02467>1,02422

Thomson KS. Antimicrob Agents Chemother. 2001;45:3548.Slide10

Therapy of ESBL Infections

Carbapenems best option

Cephalosporins:

In vitro & in vivo discordance

Failure of Ceftazidime in bacteremic patients

Reports of Ceftriaxone & Cefotaxime success

Meningitis and bacteremia

Few patients

Little data

Trimethoprim/ sulfamethoxazole

Aminoglycosides

Fluoroquinolones

Wong-Beringer A.

Pharmacotherapy

2001;21:583.Slide11

This is

Neisseria

gonorrheaSlide12

Resistance in N.gonorrhea Emerged in 1970’s Penicillin resistance

Tetracycline resistance

DOC in 1980’s became ciprofloxacin

Fluoroquinolone resistance emerged

Asia

Hawaii Californiaeverywhere else2007, CDC recommended cephalopsorinsCeftriaxone im or cefiximeSlide13

N. gonorrhea: Cephalosporin Resistance 2000-2010

www.cdc.gov/mmwr/preview/mmwrhtml/mm6026a2.htm?s_cid=mm6026a2_w#fig2Slide14

New kid on the block:New Delhi metallo-ß-lactamase-1 (NDM-1)

2009, first report

UTI after travel to India

Isolate was K. pneumoniae

Resistant to all beta-lactam drugs

E.coli possessing NDM-1 found in patient’s stool2010 USA3 cases with 3 different organisms

2011 Cases on all continents

Except Antarctica & S. AmericaSlide15

NDM-1Encodes for broad spectrum B-lactamaseResistant to all B-lactam drugs

Sensitive to tigecycline & colistin

Resides on a plasmid

Transferable between bacteria

Within a species

Across speciesPrevalence ratesUSA lowIndia 4% of enteric Gram-negative bacilliSlide16

Why the easy spread?Horizontal transferSlide17

NDM-1: It’s in the waterPrevalence study from New Dehli, India

September-October 2010

Sampled water

Seepage (puddles & rivulets)

Public tap water

221 samples (171 seepage & 50 tap H2O51 of 171 (29%) & 2 of 50 (4%) positive11 different bacteria possessed

Including V. cholera & Shigella species

Huge implications for developing world

Worldwide interconnectedness makes further spread likely

http://www.ncbi.nlm.nih.gov/pubmed/21478057Slide18

Containing NDM-1This will NOT just go away!

Infection control is paramount

High index of suspicion

Contact isolation

Good hand hygiene

Active surveillanceLimiting broad spectrum antibiotic useReduces “pressure” that enables resistant bugs to thriveReserve active agentsFew (no?) new antibiotics in pipelineSlide19

ChickungunyaSlide20

Chikungunya Background1

st

described in 1952

Outbreaks of febrile polyarthritis

Makonde word

“that which contorts or bends up”Virus was isolated in 1953Spread throughout South-Central Africa

Spread to Thailand in 1958

Now, endemic in S. Asia

Indian Ocean outbreak ongoing since 2004Slide21

Indian Ocean Outbreak

Pialoux G, Lancet, 2007;7:319-27Slide22

Epicurves Reunion & France

Pialoux G, Lancet, 2007;7:319-27Slide23
Slide24

Clinical ManifestationsPrimary infection features

Fever 86-100%

Arthralgias 96-100%

Hands, wrists & ankles

Headache 47%

Rash 40% Secondary

Chronic polyarthralgia 5-10%

Persists for months to years

Mechanism for disease unknown

Mortality <1%

Simon F, Med Clin N Am 2008;92:1323-43Slide25

Simon F, Med Clin N Am 2008;92:1323-43

Clinical ManifestationsSlide26

Pialoux G, Lancet, 2007;7:319-27

Making the DiagnosisSlide27

Treatment & PreventionSupportive therapyDEET to repel mosquitoes

Vaccine

Live attenuated vaccine candidate (TSI-GSD-218)

Phase II trials

Single dose vaccine

98% developed neutralizing antibody at day 2885% remained sero-positive at 52 weeksTrials shelved in 2002 Future uncertain

Edelman R, Am J Trop Med Hyg 2000;62(6):681-5Slide28
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Dengue VirusesFlavivirus

Single stranded, nonsegmented RNA virus

4 distinct serotypes

Each serotype provides lifelong immunity

Infection does not confer cross protection

All can cause severe manifestationsCan be infected up to 4 timesSubsequent infections may be severeMain reservoir is humans

Non-human primates may be infectedSlide30

Dengue Disease BurdenMost common arboviral disease

Endemic in 100 countries

2.5 billion persons at risk

100 million cases yearly

250,000 cases of Dengue hemorrhagic fever

25,000 deaths yearly Slide31

Aedes Mosquitoes

Highly susceptible to Dengue infection

Preferred nourishment is human blood

Thrives in urban environments

Bites during daytime

Bite is nearly imperceptibleMay bite several people to obtain a blood mealSlide32

Spread & Distribution of Dengue

http://www.who.int/csr/disease/dengue/impact/en/Slide33

Dengue in Puerto Rico 2009-11Slide34

Dengue Clinical Syndromes

Undifferentiated fever

Classic dengue fever

Severe Dengue

Dengue

hemorrhagic feverDengue shock syndromeSlide35

Classic Dengue Fever

Sudden onset fever

Headache & retro-orbital pain

Severe myalgia & arthralgia

“Break-bone fever”

Skin rash

Appears around time of defervescence

Mild hemorrhagic manifestations

Tourniquet tests

Laboratories

Leukopenia, lymphopenia & thromobocytopenia

TransaminitisSlide36

Wilder-Smith A and Schwartz E. N Engl J Med 2005;353:924-932

Tourniquet TestSlide37

Chikungunya vs. Dengue

Chikungunya

Dengue

Fever

Common

Common

Rash

Day 1-4

Day 3-7

Retro-orbital pain

Rare

Common

Myalgia

Possible

Very common

Polyarthritis

Very common

None

Tenosynovitis

Common

NoneHypotensionPossibleCommonMinor BleedingPossible CommonSequalaeChronic polyarthritisTenosynovitisRaynaud’sFatigue Slide38

Dengue Hemorrhagic Fever: CDC Case Definition

4 criteria—must meet all

Fever

Hemorrhagic manifestations

Platelet count <100,000/mm

3

“Leaky capillaries”

Hematocrit >20% above baseline)

Low albumin

Pleural or other effusionsSlide39

Dengue Shock Syndrome

4 criteria for DHF plus

Circulatory failure:

Rapid and weak pulse

Pulse pressure < 20 mm Hg

SBP <90 mmHg

Duration of shock is short

12-24 hours

Supportive care only intervention

Morality ranges from 0.2%-20%

2 deaths in USA from 1993-2000Slide40

DHF MechanismAntibody mediated enhancementCross reacting Abs bind virus

They do no neutralize bound virus

Complexes bind Fc receptors

Replicate in dendritic cells & macrophages

Viral load is increased

Killer cells & T-cell are activated“Cytokine storm” ensuesEndothelial damage & capillary leakageSlide41

Wilder-Smith A and Schwartz E. N Engl J Med 2005;353:924-932Slide42

Dengue PreventionInsect precautions are mainstayVaccines2 candidates in phase 2-3 trials

Both live attenuated viruses

Both tetravalent vaccines

Immunogenic, but not reactogenic

Field trials in planning stages

Vector controlMust be multi-modalSlide43

Sehdev P Clin Inf Dis 2002;35(9):1071–1072Slide44

Yellow Fever1

st

outbreak in New World 1648

Yet, thought to originate from Africa

Global epidemics

1793: Philadelphia 10% population died1878: Mississippi Valley 100,000 casesSanitary measures reduced burden

Serendipitous

Vector was not known at time

Virus isolated in 1927

Vaccine developed in 1928Slide45

Yellow Fever Map 2007

http://www.cdc.gov/ncidod/dvbid/yellowfever/YF_GlobalMap.htmlSlide46

Estimated Disease Burden200,000 cases per year30,000 deaths

Epidemic attack rates

30 cases per 1,000 persons

Case fatality rates

20-50% in endemic areas

Imported cases rare, but deadly6 cases USA & Europe 1996-2004

http://wwwn.cdc.gov/travel/yellowbook/ch4/yellow-fever.aspxSlide47

YF Transmission Cycle

Monath TP, Lancet ID 2001;1:11-20Slide48

Stages of Yellow Fever

Monath TP, Lancet ID 2001;1:11-20Slide49

Diagnosis & TreatmentMainstay is serologySingle positive IgM

Fourfold rise in IgG titer

PCR positive

early (days 1-6)

But, not readily available

Culture is gold standardTherapy is supportiveRibavirin has been tried, but doesn’t workImmunoglobulin not usefulSlide50

Yellow Fever Vaccine

Live, attenuated virus (17D strain)

95% effective, 10 year protection

HA, fever & myalgia

Immediate hypersensitivity (1/131,000)

Vaccine associated neurotrophic disease16/23 case age <

9 months

Vaccine associated viscerotropic disease

10 cases since 1996

Contraindications

Egg allergy & age < 9 months

MMWR 2002;51:RR-17