A Worldwide Crisis: Inappropriate Antibiotic Use & Resistant Bacterial Infections

James A. Wilde MD Associate Professor of Emergency Medicine and Pediatrics Director Pediatric Emergency Medicine Medical College of Georgia Medical Director, Georgia United Against Antibiotic Resistant Disease (GUARD)

What Causes Infections?

Infections are caused by 1 of 4 types of microbes (germs)
Virus Bacteria Parasites Fungus

75% or more of all infections less than 25% less than 1% in the US less than 1% in the US

Viruses

Parasites-need other cells to provide food and means of reproducing (sucks the life out of a cell) Attack humans by invading cells of certain tissues

Hepatitis virus: attacks the liver cells Encephalitis virus: attacks the brain cells Cold virus: attacks the throat and breathing passages Diarrhea virus: attacks the small intestine

Can live dormant in the environment for years Difficult to treat

Multiply rapidly and easily transmitted by blood and body secretions Antibiotics DO NOT WORK against viruses!

Bacteria

Can live and grow wherever they find food

Environment: mountain streams, ocean water, rotting

animal or plant, sewer, topsoil, food Humans & Animals: blood, skin, throat, lungs, urinary bladder, intestine

Good versus Bad Bacteria Some copy and grow every 20 minutes

Makes them difficult to treat: we are outnumbered

Diseases Caused by Viruses and Bacteria

Virus Common cold Diarrhea (99%) Acute Bronchitis Influenza (flu) Measles Chicken Pox AIDS Rabies Hepatitis Bacteria Urine infections Strep Throat Boils/abscesses Gangrene Some pneumonia Ear infections (half) Sinus infections (< half) Bubonic Plague Tuberculosis

How Do We Treat Infections?

Bacterial infections Immune system (white blood cells, etc) Antibiotics (Penicillin, etc.) help to kill bacteria

Viruses Immune system Anti-viral medications: not very helpful Antibiotics have NO EFFECT against viruses!

How do Antibiotics Kill Bacteria?

Interfere with bacterial metabolism or reproduction

Crowbar in a clock tower

Viruses have completely different metabolism and reproductive mechanisms

Crowbar has no effect on a waterfall

Bacteria are killed by antibiotics, but no antibiotic is effective against all bacteria

Must match the antibiotic to the disease

Fact: Bacteria are the cause of the

majority of deaths due to sepsis, meningitis, and pneumonia in the U.S. But: Most infections are due to viruses. Therefore: Most infections are not serious or life threatening.

Fact: Virus
Most viral infections get better all by themselves in 1-3 weeks No medications are required for resolution of colds, flu, stomach virus Treat symptoms with Over the Counter medications & TLC (moms chicken soup)

Treatment of Acute Bronchitis

100 80
No Antibiotic (+) Antibiotic

% Patients

60 40 20 0 0 2 4 6 8 10

12

14

16

18

Days with cough

Stott, BMJ 1976

A Doctors Approach to Infections

Fever does not cause brain damage

Underlying source of the fever can cause brain damage

A viral infection is a nuisance A bacterial infection can be deadly SO The doctors task is to decide who has infection due to a virus and who has infection due to a bacteria.

Antibiotic Prescription Rate: Private Physicians

Colds: 51% Upper respiratory infections: 52% Bronchitis: 66%

These antibiotics are unnecessary!!!

Gonzales et al., JAMA, 1997

So Why Do Doctors Give Antibiotics For Viral Infections?

They think YOU want an antibiotic, i.e. patients have been trained to expect them Time: writing a prescription is easier than explaining why you dont need one Doctors think the antibiotics will prevent a secondary bacterial infection (theyre wrong) They misdiagnose a viral infection for a bacterial infection: Sinusitis versus Cold Medicolegal concerns

Problems With Inappropriate Use of Antibiotics

They dont help the patient at all when used for the wrong disease/illness Side effects: diarrhea, rash, allergy Unnecessary expense: 75% of outpatient antibiotics are used for respiratory infections (viruses)

Development of resistance: the antibiotic

wont work when you really DO need it for a bacterial infection

Penicillin no longer works for impetigo or urine infections

Antibiotics Used to Work

What Happened???

HISTORICAL PERSPECTIVE

Antibiotics introduced 60 years ago Bacteria from pre-antibiotic era had virtually no resistance genes Staph aureus (skin, wound infections) was universally treatable with Penicillin at the time of its release

Chronology of Development of Antibiotic Resistance

Antibiotic
Penicillin Streptomycin Tetracycline Erythromycin Gentamicin Vancomycin

Year introduced
1942 1947 1952 1955 1967 1956

Resistance identified
1940 1947 1956 1956 1970 1987

How Bacteria Become Resistant

Susceptible Bacteria Resistant Bacteria

Resistance Gene Transfer

New Resistant Bacteria

Resistant Genes

More than 400 resistance genes have been identified These genes allow the bacteria to shield themselves from the antibiotic Resistance genes can be transferred from one bacterial species to another: spread of resistance is RAPID

Remember: Some bacteria can copy themselves (double) every 20 minutes!

Decreased entry

Efflux pump Altered target site

Mechanisms of Resistance
Enzymatic degradation

Bypass pathway

Evolution of Drug Resistance in

S. aureus
Penicillin Methicillin MethicillinPenicillin-resistant S. aureus resistant [1950s] [1970s] S. aureus S. aureus (MRSA)
[1997]
Vancomycin

[1990s]

Vancomycin-

resistant
S. aureus

[ 2002 ]

Vancomycin intermediateresistant S. aureus (VISA)

Vancomycin-resistant enterococci (VRE)

Proportion of S. aureus Nosocomial Infections Resistant to Oxacillin (MRSA) Among Intensive Care Unit Patients, 1989-2003*
70

Percent Resistance

60 50 40 30 20 10 0
1989 1991 1993 1995 1997 1999 2001 2003

Year
*Source: NNIS System, data for 2003 are incomplete

Emergence of Vancomycin Resistant Enterococci

30
Non-Intensive Care Unit Patients

Percent Resistance

25 20 15 10 5 0

Intensive Care Unit Patients

19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00
Source: NNIS Data

Clinical Significance of Antibiotic Resistance

Therapeutic failures and relapse Facilitates spread in the hospital under antibiotic pressure Need to use more costly and toxic agents The emergence of untreatable pathogens

US New Antibacterial Agents

Year 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 No. Approved 20 3 1 0 2 4 2 0 3 1 2 0 2 Multiple agents Temafloxacin, lomefloxacin, cefpodoxime Piperacillin/Tazobactam Lowest number of new agents (22) since 1988 Dirithromycin, ceftibutin Meropenem, levofloxacin, sparfloxacin, Cefepime Grepafloxacin, Trovafloxacin Rivaled 1994 Dalfopristin/quinupristin, gatifloxacin, moxifloxacin Linezolid Ertapenem, ceftidoren 89 drugs approved, no antibacterial agents Daptomycin, gemifloxacin Agents

The development of new antibiotics without having mechanisms to insure their appropriate use is much like supplying your alcoholic patients with a finer brandy.
- Dennis Maki, 1998
- From Managing the Minefield Satellite Symposium Annual Meeting of the Infectious Diseases Society of America

It gets worse
Farmers routinely use antibiotics in animal feed!

Why Use Antibiotics in Animal Feed?

Promotes growth Decreases amount of feed needed Prevents infectious diseases (examples?) Facilitates confinement housing Lowers cost to consumer

ANTIMICROBIAL RESISTANCE: The role of animal feed antibiotic additives

48% of all antibiotics by weight is added to animal feeds to promote growth. Results in low, sub-therapeutic levels which are thought to promote resistance. Farm families who own chickens feed tetracycline have an increased incidence of tetracycline resistant fecal flora Chickens at Spanish supermarkets have >90% of cultured campylobacter resistant to quinolones 39% of enterococci in the fecal flora of pigs from the Netherlands is resistant to vancomycin vs 0% in Sweden. (Sweden bans antibiotic additives in animal feed)

How does this affect me?

Animals harbor the same bacteria on their skin and in their guts as humans The antibiotics used in animal feed are similar to those used in humans Resistant bacteria develop in animals the same as in humans Resistant bacteria are spread from animals to humans

Decrease in VRE After Removing Avoparcin From Animal Feed

EID 1999; Vol 5

National Effort to Stop Unwarranted Antibiotics

Surveillance
Agency for Prevention and Control Care Research and Health Quality Department of Defense

Research Product Development Education 28 Coalitions in U.S.

Health Care Financing Administration

Department of Agriculture

Environmental Protection Agency Department of Health Resources and Services Veterans Affairs Administration

Local Efforts: GUARD Coalition

Georgia United Against Antibiotic Resistant Disease

2002-2006: Funded by the Centers for Disease Control and Prevention (CDC), part of Get Smart program 2002-Spring 2005: Oversight by Georgia Department of Public Health Spring 2005: Officially became part of and managed by the Medical College of Georgia

Medical Director: Jim Wilde, MD, FAAP (MCG faculty)

GUARD Mission
The GUARD Coalition seeks to reduce antibiotic-resistant diseases by decreasing inappropriate antibiotic use through a collaboration of community partners:

GUARD Coalition Members

Medical Association of Georgia GA chapter American Academy of Pediatrics GA chapter American Academy of Family Physicians Blue Cross Blue Shield Georgia Hospital Association GA Assn Infection Control Nurses

GA Department of Public Health PHARMA US Centers for Disease Control and Prevention Medical College of Georgia Emory University GA PTA many individual physicians, nurses and other health professionals

GUARD Goals

Community education about appropriate use of antibiotics Physician education

How to recognize bacterial infections Rising rates of resistant bacteria New antibiotics and their proper use

Create and distribute educational materials

So, what can I do?

Educate yourself: most infections dont require antibiotics Talk to your doctor to see if antibiotics are appropriate for you and/or your child Dont use leftover antibiotics Dont use someone elses antibiotics Follow instructions-take them properly Spread the wordnot the bacteria!

His life is in OUR hands

The ravaging epidemic of AIDS has shocked the worldWe will face similar catastrophes againWe have too many illusions that we cangovern the remaining vital kingdoms, the microbes, that remain our competitors of last resort for dominion of the planet
1988, Dr. Joshua Lederberg, Nobel Laureate

VII. A New Bug on the Block: Community Associated Methicillin Resistant Staph aureus (CA-MRSA)

Staph is a common bacteria found on the skin of many people

Staph epidermidis Staph aureus

Designated MRSA if resistant to methicillin, a synthetic penicillin introduced in the early 1960s

In most cases this Staph does no harm

CA-MRSA

First noted as emerging problem in late 1990s Increasing rate of MRSA infections in patients with none of the usual risk factors
Initially noted in prisons Sports teams

Getting national attention 2002/2003 Unusual sensitivity pattern: did not exhibit multidrug antibiotic resistance typical of earlier strains of hospital acquired MRSA (HA-MRSA)

(CA-MRSA, cont)
New Staph strain now referred to as Community Associated MRSA, or CA-MRSA Primarily USA 300 clone on PFGE, also USA 400

First isolated in 2000

Many people are colonized but exhibit no symptoms (carrier) Panton-Valentine leukocidin (PVL) toxin: lethal to neutrophils, induces abscess formation

90% of CA-MRSA, < 5% of HA-MRSA

MRSA Summary
Health care associated: HA-MRSA Risk factors (hospitalization, nursing home, surgery, etc) Community-associated: CA-MRSA Poorly defined risk factors (children/day care, prisons, sports teams, MSM, Native Americans)

Multidrug Resistant >90% erythromycin, clindamycin, quinolone (FQ) resistant Different PFGE PVL negative SCC mec I, II, III

-lactam resistant; often resistant to erythromycin; more susceptible to other agents (clindamycin, TMP/Sulfa, FQ) PFGE USA300, USA 400 PVL present SEC mec IV

CA-MRSA: Epidemiology

Has quickly become the predominant Staph aureus species in most communities

King, Blumberg, et al Ann Int Med Nov 2003

Surveillance Aug to Nov 2003, Atlanta (Grady Hosp) MRSA caused 72% of all skin and soft tissue infections 63% of all MRSA was CA-MRSA

Medical College of Georgia data similar by 2005

Prevalence of MRSA as cause of SSTI in Adult ED Patients

EMERGEncy ID Net, Moran GJ, et al, SAEM 2005

7/13 (54%)

11/28 (39%)

59%
98% PVL+ 97% USA300 72% 300-0114

3/20 (15%)

32/58 (55%)
43/58 (74%) 17/25 (68%)

24/47 (51%) 25/42 (60%) 18/30 (60%) MSSA 17%

42% PVL+ 31% USA300

23/32 (72%)
46/69 (67%)
Kindly provided by Rachel Gorwitz, CDC

MRSA in Medical College of Georgia (Adult Hospital) 1993-2005

cases/1000 patient days

5.00 4.00 3.00 2.00 1.00 0.00

19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05

Nosocomial

Entered with

MRSA in the CMC, Medical College of Georgia 1999-2005

8.00
cases/1000 patient days

Nosocomial

Entered with

7.00 6.00 5.00 4.00 3.00 2.00 1.00 0.00 1999 2000 2001 2002 2003 2004 2005

Nasal carriage of Staph aureus Creech et al, Ped Inf Dis J 2005: Examined nasal carriage of Staph in children in Nashville

2001
29% colonized with Staph aureus 0.8% colonized with MRSA

2004
36.4% colonized with Staph 9.2% colonized with MRSA

Risk factors for CA-MRSA Children Breaks in Skin/abrasions Sharing towels/razors Incarceration Men having sex with men Contact sports participants

Clinical Manifestations, CA-MRSA

Vast majority are skin and soft tissue infections (SSTI) Many SSTI come in the form of abscesses
Multiple abscesses may be present Recurrence common ****Often mistaken for a spider bite

Increasing number of invasive infections over the past 2-3 years

? Spider Bite?
Slide provided by Melissa Tobin DAngelo, Georgia DHR

Carbuncle
Slide provided by Melissa Tobin DAngelo, Georgia DHR

Folliculitis
Slide provided by Melissa Tobin DAngelo, Georgia DHR

Abscess
Slide provided by Melissa Tobin DAngelo, Georgia DHR

Cellulitis with Abscess

Slide provided by Jim Wilde MD

CA-MRSA: Changing Patterns

Seybold, Blumberg et al., Clinical Inf Dis, March 2006: CA-MRSA as a cause of blood stream infections (BSI) 116 cases MRSA BSI over 7 months, 2004
MRSA USA 300 accounted for 34% 20% of nosocomial MRSA BSI were USA 300

Crude in-hospital mortality 22%

(changing patterns, continued)

MMWR, April 13 2007

Report of severe community acquired pneumonia due to CA-MRSA, LA and GA 10 patients, median age 17 y (eight < 30y) All had influenza-like illness, 6 confirmed flu 6/10 died, median 3.5 days after symptom onset Five isolates studied by CDC, all USA-300

National Prevalence study of MRSA in US Healthcare Facilities: APIC Report June 2007 Survey done in 1,237 hospitals in the US Oct/Nov 2006 Symptomatic patients (infections) and targeted high risk patients Overall rate 4.6%

Majority were HA-MRSA

Invasive MRSA infections in the US. Klevens et al., Journal of the American Medical Association (JAMA) October 19, 2007 Surveillance data collected from 9 US communities Extrapolation to US population Estimated 18,650 deaths per year

Over 90% of deaths due to HA-MRSA

VI. Management of CA-MRSA SSTI

Abscesses should be drained

Drainage alone in many cases is definitive therapy Strong recommendation to obtain culture

Helps to define local epidemiology/resistance pattern

Antibiotics in selected cases

Abscess greater than 5 cm diameter Significant area of cellulitis Systemic symptoms

For impetigo or simple cellulitis, consider antibiotic therapy directed at CA-MRSA Most CA-MRSA infections are easily treated if managed appropriately

Suggested Antibiotics for CA-MRSA Outpatient

Trimethoprim/Sulfamethoxisole

Cellulitis: Add beta-lactam to cover for strep

Clindaymcin Doxycycline Avoid quinolones if possible (Cipro, Levofloxacin) DO NOT use Rifampin as monotherapy

CDC recommendation: If local CA-MRSA prevalence exceeds 15%, beta-lactams (penicillins and cephalosporins) should not be used as monotherapy for skin and soft tissue infections

Inpatient management
For severe or life-threatening infections suspected to be due to CA-MRSA, initial empiric therapy should include Vancomycin PLUS a betalactamase resistant beta-lactam antimicrobial agent
Oxacillin Nafcillin Ampicillin/Sulbactam

Ref: 2003 Red Book, American Academy of Pediatrics: page 567

Parenteral (IV) antibiotics for MRSA: options

Vancomycin

Not as active as beta-lactam antibiotics against susceptible Staph aureus

Linezolid Quinupristin/Dalfopristin (Synercid) Daptomycin

Deactivated by Surfactant: Not for pneumonia

Tigacycline

Decolonization efforts Intranasal Mupirocin Chlorhexidine body washes

Efficacy data are lacking Reacquisition common Generally not recommended May be reasonable in certain situations

Multiple documented recurrences Ongoing transmission in well-defined, closely associated cohort such as a household, sports team, etc.

Infection control measures: Athletic teams Good hand hygiene critical Clean shared athletic equipment before use No sharing of bath towels, soap, razors No participation in contact sports if draining sores or impetigo are present Keep a clean, dry bandage over draining sores Cleanse contaminated surfaces with 1:1000 solution bleach (1 tbsp bleach/1 quart water) or EPA-registered hospital detergent/disinfectant

Public Health and CA-MRSA CDC does NOT recommend exclusion from school for those with MRSA Decontamination of buildings/classrooms generally not warranted unless multiple infections Georgia MRSA Task Force fact sheet

GUARD web site: www.guard-ga.org State Health Department: www.health.state.ga.us/mrsa/

Tips for the public See your doctor for boils or pustules or tender/red/swollen areas on the skin Do not attempt to drain abscesses at home If fever present, or if sore is enlarging rapidly, seek medical care immediately Dont attempt self treatment with old antibiotics Recurrence is common; follow up with your MD

For More Information on GUARD

Contact
Dr. Jim Wilde MD, FAAP Director, GUARD Coalition (706) 533-2925 jwilde@mcg.edu

www.guard-ga.org