Antibiotic Resistant Pathogens in the Health Care Setting

Gonzalo Bearman MD, MPHAssistant Professor of Medicine, Epidemiology and Community HealthAssociate Hospital EpidemiologistVirginia Commonwealth University

Focus On Infection Control

VA APIC Conference 2005

Outline• Nosocomial Infections

– Background, Epidemiology– Changing Paradigm

• Important Nosocomial Pathogens– MRSA– CA MRSA– VRE– MDR- GNRs– ESBL producing organisms– C.difficile

• Importance of hand hygiene in decreasing cross transmission– Alcohol based hand sanitizers

• Isolation Categories– Contact Isolation– Gowns and gloves

• Compliance with IC guideline– The importance of process measure feedback

Nosocomial Infections

• 5-10% of patients admitted to acute care hospitals acquire infections– 2 million patients/year– ¼ of nosocomial infections occur in ICUs– 90,000 deaths/year– Attributable annual cost: $4.5 – $5.7 billion

• Cost is largely borne by the healthcare facility not 3rd party payors

Weinstein RA. Emerg Infect Dis 1998;4:416-420.Jarvis WR. Emerg Infect Dis 2001;7:170-173.

Major Sites of Nosocomial Infections

• Urinary tract infection

• Surgical site infection

• Bloodstream infection

• Pneumonia (ventilator-associated)

Nosocomial Infections

• 70% are due to antibiotic-resistant organisms

• Invasive devices are more important than underlying diseases in determining susceptibility to nosocomial infection

Burke JP. New Engl J Med 2003;348:651-656.Safdar N et al. Current Infect Dis Reports 2001;3:487-495.

Nosocomial Infections in the US

1975 1995

Number of admissions (millions) 37.7 35.9

Number of patient days (millions) 299.0 190.0

Average length of stay (days) 7.9 5.3

Number of nosocomial infections (millions)

2.1 1.9

Incidence of nosocomial infections(per 1,000 patient-days)

7.2 9.8

Burke JP. New Engl J Med 2003;348:651-656.

Attributable Costs of Nosocomial Infections

Cost per Infection

Wound infections $3,000 - $27,000

Sternal wound infection $20,000 - $80,000

Catheter-associated BSI $5,000 - $34,000

Pneumonia $10,000 - $29,000

Urinary tract infection $700

Nettleman M. In: Wenzel RP, ed. Prevention and Control of Nosocomial Infections, 4th ed. 2003:36.

Shifting Vantage Points on Nosocomial Infections

Gerberding JL. Ann Intern Med 2002;137:665-670.

Many infections are inevitable, although

some can be prevented

Each infection is potentially

preventable unless proven otherwise

Antibiotic Resistant Pathogens in the Hospital Setting

NNIS Summary 2004

Fig 1. Selected antimicrobial-resistant pathogens associated with nosocomial infections in ICU patients, comparison of resistance rates from January through December 2003 with 1998 through 2002, NNIS System. CNS, Coagulase-negative staphylococci; 3rd Ceph, resistance to 3rd generation cephalosporins (either ceftriaxone, cefotaxime, or ceftazidime); Quinolone, resistance to either ciprofoxacin or ofloxacin. Percent (%) increase in resistance rate of current year (January-December 2003) compared with mean rate of resistance over previous 5 years (1998-2002): [(2003 rate – previous 5-year mean rate)/previous 5-year mean rate] × 100.

American Journal of Infection Control Volume 32, Issue 8 , December 2004, Pages 470-485

MRSA (Methicillin Resistant S.aureus)

•Appeared in 1980s•50-70% of hospital S.aureus isolates are MRSA

•Carrier state (colonization)- asymptomatic•Reduce transmission by detecting and treating all infected

and colonized patients•Drug of choice is vancomycin•Patients with MRSA infection/colonization are placed on contact isolation•Recent reports of a vancomycin resistant strains of S.aureus•Certain to be an increasingly difficult management problem

Methicillin-resistant–Staphylococcus aureus

Hospitalizations, United States • National Hospital Discharge Survey used to calculate the

number of US hospital discharges listing S. aureus–specific diagnoses

• From 1999 to 2000:– 125,969 hospitalizations with a diagnosis of MRSA infection

occurred annually• 31,440 for septicemia (BSI)

• 29,823 for pneumonia

• 64,706 for other infections

• 3.95 per 1,000 hospital discharges

• National burden of serious MRSA disease is substantial

Kuehnert MJ, Hill HA, Kupronis BA, Tokars JI, Solomon SL, Jernigan DB. Methicillin-resistant–Staphylococcus aureus Hospitalizations, United States. Emerg Infect Dis [serial on the Internet]. 2005 Jun. Available from http://www.cdc.gov/ncidod/EID/vol11no06/04-0831.htm

Community Acquired MRSA

Comment

Epidemiology CA-MRSA infections were first recognized in the 1980s

Persons with CA-MRSA infections are typically younger and healthier than persons with healthcare-associated MRSA.

CA-MRSA bacteria are usually susceptible to more types of antibiotics than are healthcare-associated strains of MRSA

• Typically susceptible to Bactrim, Clindamycin, Doxycycline

Clinical

Presentation

Most infections caused by Staphylococcus aureus are skin and soft tissue infections such as abscesses or cellulitis

Necrotizing pneumonia

VRE (vancomycin resistant enterococci)

• Enterococcus faecalis and E. faecium•E. faecium is the most frequently isolated species of VRE in hospitals and typically produces high vancomycin (>128 µg/ml) and teicoplanin (>16 µg/ml) minimum inhibitory concentrations (MICs)

• Normal inhabitants of bowel• Can cause UTI, BSI, VAP and wound infections in critically ill patients •Cross infection via contaminated equipment documented

•Thermometers

MRSA and VRE• Prevention of MRSA/VRE infections is based upon standard

infection control precautions including: • Hand Washing • Wash hands immediately after gloves are removed, between patient

contacts and between tasks and procedures.• Gloving – contact isolation• Wear gloves when touching blood, body fluids and contaminated

items• Remove gloves between patient contacts and wash hands

immediately. • Gowning –contact isolation• Wear a gown during procedures that are likely to generate splashes

or droplets of blood and body fluids. • Dedicated Patient Care Equipment • Appropriate cleaning, disinfection and sterilization of patient care

equipment are important in limiting the transmission of organisms.

MDR Gram Negative Rods

• MDR gram negative rods are defined as isolates that are susceptible to no more than one class of antimicrobial agents (excluding colistin).

• Increasingly problematic– Acinetobacter baumanii– Stenotrophomonas maltophilia– Pseudomonas aeruginosa

Application of control measures for infections caused by multi-resistant gram-negative bacteria in intensive care unit patients

Prospective study of ICU patients in the Hospital Sao Paulo, between March-June 1997 and March-June 1998.

Surveyed nosocomial infections with multi-resistant microorganisms:

•A.baumannii and P.aeruginosa: resistant to :aminoglycosides, quinolones, third-generation cephalosporins, and carbapenems.

Mem. Inst. Oswaldo Cruz vol.99 no.3 Rio de Janeiro May 2004

Application of control measures for infections caused by multi-resistant gram-negative bacteria in intensive care unit patientsPromotion of hand hygiene (PVP-I or chlorexidine) before and after contact

with the patient

Application of contact isolation measures

Daily surface cleaning and disinfection with alcohol at 70%

Separation of articles and equipment for exclusive use of the patient

Study showed significant increase in percentage of multi-resistant pathogens in second period vs first period

UTI with multi-resistant increased from 22.7% to 30%, pneumonia 8.3% to 33.3% , and in BSI from 4.7% to 60%

Infections with MDR GNR are difficult to manage and will likely require more than just stringent IC practice

Mem. Inst. Oswaldo Cruz vol.99 no.3 Rio de Janeiro May 2004

Relatively Poor Outcome after

Treatment of Clostridium difficile Colitis

with MetronidazoleProspective, observational study of 207 patients who were treated with metronidazole for C. difficile colitis

•103 patients (50%) were cured by the initial course of therapy and had no recurrence of disease.

•22% continued to have symptoms of colitis for 10 days despite treatment

• 28% responded initially but had a recurrence within

the ensuing 90 days.

•The mortality rate higher among patients who did not

respond fully to an initial course of therapy, compared with those who did (33% vs. 21%; P < .05)

Clinical Infectious Diseases    2005;40:1586-1590

Increasing Risk of Relapse after Treatment of

Clostridium difficile Colitis in Quebec, Canada

Clinical Infectious Diseases    2005;40:1591-1597

Kaplan-Meier plots of the 60-day probabilities of recurrence among patients with Clostridium difficile associated

diarrhea treated with only metronidazole, comparing 1991-2002 to

2003-2004 (top).

Treatment with only

vancomycin during 1991 2002 to 2003-2004 (bottom)

Clostridium difficile

• Because of the increasingly poor response to therapy, additional approaches to prevention and/or treatment

of C. difficile colitis are in order• Newer therapies

– nitazoxanide or tinidazole– probiotics, such as Saccharomyces boulardii and

Lactobacillus species

• Stringent application of infection control measures– Contact isolation– Meticulous hand hygiene– Thorough terminal disinfection of patient rooms

• (sporicidal agent)

The ABC’s of ESBL for Infection Control Nurses: -Extended-Spectrum Beta-Lactamases-

Epidemiology

• Today, 30 – 50% of E. coli are resistant to ampicillin and amoxicillin due to a beta-lactamase

• ESBLs have been reported for E.coli, Klebsiella, Enterobacter, Proteus,Pseudomonas, Salmonella, Serratia

Beta-Lactamases: What are they ?

• Enzymes produced by certain bacteria that provide resistance to certain antibiotics

• Produced by both gram positive and gram negative bacteria

• Found on both chromosomes and plasmids

Beta-lactamases

• Are primary mode of resistance to beta-lactam antibiotics

• Produced by some gram positive bacteria and virtually all gram negative bacteria

ESBL?• Resistance that is produced through the actions of

beta-lactamases. • Extended spectrum cephalosporins, such as the

third generation cephalosporins, were originally thought to be resistant to hydrolysis by beta-lactamases!

• Not so!– mid 1980's it became evident that a new type of beta-

lactamase was being produced by Klebsiella & E coli that could hydrolyze the extended spectrum cephalosporins.

– These are collectively termed the• 'extended spectrum beta-lactamases' (ESBL's)

Mechanism of Action

• Hydrolysis of beta-lactam ring of basic penicillin structure

• Hydrolysis = adding a molecule of H2O to C-N bond with enzyme action– This opens up the ring, thus making the drug

ineffective!ineffective!

Plasmids

• Rings of extrachromosomal DNA

• Can be transferred between different species of bacteria conjugation

• Carry resistance genes

• Most common and effective mechanism of spreading resistance from bacteria to bacteria

Bacterial Conjugation

Beta-lactam Antibiotic Examples

• Penicillins:– Penicillin, amoxicillin, ampicillin

• Cephalosporins:– Ancef, Rocephin, Keflex, Cefotan

• Carbapenems:– Imipenem, meropenem

Beta-lactamase inhibitor • Clavulanic acid + amoxicillin = Augmentin• Clav. Acid + ticarcillin = Timentin• Sulbactam + ampicillin = Unasyn• Tazobactam + piperacillin = Zosyn

Good News: Beta-lactamase inhibitors inhibit the beta lactamase thereby not allowing the molecule to hydrolyze the antibiotic. Most ESBLS remain susceptible to Beta-lactamase inhibitors

Bad News: some ESBL producing bacteria produce large amounts of beta-lactamase thereby overwhelming the beta-lactamase inhibitors

The story is more complicated….• Multiple antimicrobial resistance is often a characteristic

of ESBL producing gram-negative bacteria.• Ceftazidime• Cefotaxime• Ceftriaxone• Aztreonam

• Genes encoding for ESBLs are frequently located on plasmids that also carry resistance genes for:

• Aminoglycosides• Tetracycline• TMP-SULFA• Chloramphenicol• Fluoroquinolones

NCCLS ESBL Screening

• For isolates:– K.pneumoniae, E.coli and K.oxytoca :– 1st step- screen using:

• Ceftazidime, ceftriaxone, cefotaxime, cefpodoxime, or aztreaonam

– 2nd Step: If MIC> 2 mcg/ml then:• Ceftazidime and cefotaxime alone and in combination with

clavulanate • Positive test: greater than a three-fold reduction in MIC for

combination versus single agent– ESBL status of organism is now highly likely

Take home message:ESBLs are harbingers of multidrug resistance

What are the clinical implications?

• Can result in treatment failure– Morbidity and mortality

• Several outbreaks have occurred • If an ESBL is detected, all penicillins,

cephalosporins, and aztreonam should be reported as “resistant”, regardless of in vitro susceptibility test results

Management of ESBL infections

• Pharmacotherapy:– Treatment of choice for serious infections

• Carbapenems– Stable in the presence of most beta-lactamases– Examples

» Imipenem» Meropenem

• Restrict the use of 3rd generation cephalosporins.

Infection Control?

As infection control nurses your job is to ensure that adequate precautions are taken to minimize the risk of cross transmission!– Contact precautions

• Cohort patients during outbreaks

– Promote meticulous hand hygiene practices– Reminders to HCW staff about Patient ESBL status

• Electronic flagging of medical record• Placing stickers on charts

– When are contact precautions discontinued?• No specific guidelines:

– Resolution of infectious process

Nosocomial Drug Resistant Pathogens:• Nosocomial pathogens of continued or

increasing concern– MRSA– CA-MRSA– VRE– C.difficile– MDR GNR– ESBL producing organisms

30%-40% of all Nosocomial Infections are Attributed to

Cross Transmission

The inanimate environment is a reservoir of pathogens

~ Contaminated surfaces increase cross-transmission ~

Abstract: The Risk of Hand and Glove Contamination after Contact with a VRE (+) Patient Environment. Hayden M, ICAAC, 2001, Chicago, IL.

X represents a positive Enterococcus culture

The pathogens are ubiquitous

The inanimate environment is a reservoir of pathogens

Recovery of MRSA, VRE, C.diff CNS and GNR

Devine et al. Journal of Hospital Infection. 2001;43;72-75

Lemmen et al Journal of Hospital Infection. 2004; 56:191-197

Trick et al. Arch Phy Med Rehabil Vol 83, July 2002

Walther et al. Biol Review, 2004:849-869

The inanimate environment is a reservoir of pathogens

Recovery of MRSA, VRE, CNS. C.diff and GNR

Devine et al. Journal of Hospital Infection. 2001;43;72-75

Lemmen et al Journal of Hospital Infection. 2004; 56:191-197

Trick et al. Arch Phy Med Rehabil Vol 83, July 2002

Walther et al. Biol Review, 2004:849-869

The inanimate environment is a reservoir of pathogens

Recovery of MRSA, VRE, CNS. C.diff and GNR

Devine et al. Journal of Hospital Infection. 2001;43;72-75

Lemmen et al Journal of Hospital Infection. 2004; 56:191-197

Trick et al. Arch Phy Med Rehabil Vol 83, July 2002

Walther et al. Biol Review, 2004:849-869

Transfer of VRE via HCW Hands

Duckro et al. Archive of Int Med. Vol.165,2005

16 transfers (10.6%) occurred in 151 opportunities.

•13 transfers occurred in rooms of unconscious patients who were unable to spontaneously touch their immediate environment

Alcohol Based Hand Sanitizers

• CDC/SHEA hand antiseptic agents of choice– Recommended by CDC based on strong

experimental,clinical, epidemiologic and microbiologic data

– Antimicrobial superiority• Greater microbicidal effect

• Prolonged residual effect

– Ease of use and application

Alcohol based hand hygiene solutionsQuick Easy to use

Very effective antisepsis due to bactericidal properties of alcohol

Impact of alcohol based hand sanitizers at VCU: can this improve hand hygiene?

Arch Intern Med. 2000;160:1017-1021.

Hand Hygiene Educational Program Implemented

Direct Observation of Hand Hygiene

Incremental Increase in Alcohol Dispensers

Study Algorithm

Arch Intern Med. 2000;160:1017-1021.

•Improvement in Hand Hygiene Compliance

Results

Hand hygiene practice can be improved with education and greater accessibility of alcohol hand sanitizers

Hand Hygiene

• Single most important method to limit cross transmission of nosocomial pathogens

• Multiple opportunities exist for HCW hand contamination– Direct patient care– Inanimate environment

• Alcohol based hand sanitizers are ubiquitous– USE THEM BEFORE AND AFTER PATIENT

CARE ACTIVITIES

Types of Isolation Precautions

Transmission-based Precautions-for patients with documented or suspected infections

-3 Types:

airborne, droplet and contact

Transmission-based Precautions-for patients with documented or suspected infections

-3 Types:

airborne, droplet and contact

Standard Precautions-Apply to all Patients

--Replace Universal Precautions

Standard Precautions-Apply to all Patients

--Replace Universal Precautions

Contact Precautions for drug resistant pathogens.

Gowns and gloves must be worn upon entry into the patient’s room

Contact Precautions

• MRSA

• CA-MRSA

• VRE

• MDR GNR

• ESBL producing organisms

• C.difficile

Gown and Glove use for Infection Control

Glove Use for Infection ControlVariable Rationale Comment

Gloves

Prevent exposure to

bloodborne pathogens

Prevent contamination of

hands with drug resistant

pathogens during patient

care activities

Even with proper glove use, hands may become contaminated during the removal of the glove or with micro-tears that allow for microorganism transmission

Glove use should not be used

as a substitute for hand

hygiene

Gown Use for Infection ControlVariable Rationale Comment

Gowns

Several studies have

documented colonization

of healthcare worker

apparel and instruments

during patient care

activities without the use

of gowns

The use of gloves and

gowns is the convention

for limiting the cross

transmission of

nosocomial pathogens,

however, the incremental

benefit of gown use, in

endemic settings, may be

minimal

What about the role of Universal Gloving For All Patient Care?

Feedback of infection control process measures

Quality Improvement Initiative to Improve Compliance with Infection Control Practice

Measurement and feedback of infection control process measures in the intensive care unit: impact on compliance

Mezgebe Berhe MD1, Mike Edmond MD, MHA, MPH1,2, Gonzalo Bearman MD, MPH1,2

Divisions of Infectious Diseases1 and Quality Health Care2

Department of Internal Medicine

Virginia Commonwealth University School of Medicine

Richmond, VA, USA

-Measurement and feedback of infection control process measures in the intensive care unit: impact on compliance.

Mezgebe Berhe MD1, Mike Edmond MD, MHA, MPH1,2, Gonzalo Bearman MD, MPH1,2

• To measure selected infection control process measures

• To feedback the results of process indicator measurement to ICU leadership

• To assess the impact of feedback on compliance with infection control process measures

Measurement and feedback of infection control process measures in the intensive care unit: Impact on compliance

• Selected Infection Control Process Measures:– Hand Hygiene– Femoral Catheter use as proportion of CVC days– Proportion of Head of bed (HOB) elevations in medical

(MRICU) and Surgical (STICU) Intensive Care Units• All Data Collected by ICPs

– Baseline data- April-June 2004– Follow up- 3rd, 4th quarters of 2004, 1st quarter 2005– Baseline and follow up data presented to ICU nurses

and Physician staff

Mezgebe Berhe MD1, Mike Edmond MD, MHA, MPH1,2, Gonzalo Bearman MD, MPH1,2

Measurement and feedback of infection control process measures in the intensive care unit: impact on compliance

Process Measure

MRICU STICU

Baseline

Q2-2004

Q3

(2004)

Q4

(2004)

Q1

(2005)P

value*

Baseline

Q2-2004

Q3

(2004

Q4

(2004)

Q1

(2005)P

value*

HH %

Opp

14/44

(32%)

31/91

(37%)

33/91

(36%)

50/108

(46%)

0.101 19/38

(50%)

42/80

(53%)

40/80

(50%)

49/100

(49%)

0.916

HOB %

Opp

28/51

(55%)

320/333

(96%)

450/454

(99%)

551/556

(99%)

<0.001 20/43

(47%)

229/307

(75%)

389/488

(79%)

275/361

(76%)

<0.001

Fem. CVC

% of Days

195/1093

(18%)

130/769

(16%)

80/879

(9.1%)

51/951

(5.4%)

<0.001 93/1109

(8.4%)

49/970

(5.1%)

14/1077

(1.3%)

26/920

(2.8%)

0.01

Mezgebe Berhe MD1, Mike Edmond MD, MHA, MPH1,2, Gonzalo Bearman MD, MPH1,2

0

10

20

30

40

50

60

70

80

90

100

Q1-04 Q2-04 Q3-04 Q4-04 Q1-05 Q2-05

0

1

2

3

4

5

6

7

8

HOB compliance Pneumonia cases/1,000 ventilator-days

Head of Bed Elevation in VCU Medical ICU:Effect of Feedback

% C

om

pli

ance

wit

h H

OB

el

evat

ion

Baseline;no feedback

Performance feedback quarterly

Pn

eum

on

ia cases/1,000 ventilato

r-d

ays

Measurement and feedback of infection control process measures in the intensive care unit: impact on compliance

• Feedback of process measures:• lowered the use of femoral catheters• Improved the proportion of elevated HOBs in

both ICUs• There was no significant improvement in hand

hygiene.• System level changes such as catheter

placement and HOB elevation appears to be impacted by feedback whereas individual level practices such as hand hygiene were not affected

Mezgebe Berhe MD1, Mike Edmond MD, MHA, MPH1,2, Gonzalo Bearman MD, MPH1,2

Conclusion

• Antimicrobial resistant pathogens are becoming increasingly problematic in acute care settings– MRSA,VRE, CA-MRSA, MDR GNRs, C.difficile

and ESBL producing GNR

• Paradigm Shift in Nosocomial Infections– Each infection is potentially preventable unless

proven otherwise• Healthcare facilities must have up to date IC programs

and strive for maximum compliance with IC guidelines

Conclusion

• IC measures to limit cross transmission of drug resistant pathogens– Hand Hygiene

• Alcohol based hand sanitizers

– Contact Precautions• Gown• Gloves

– Surveillance and feedback of IC process measures to maximize adherence to guidelines