Controlling Antimicrobial-Resistant Infections: MRSA & VRE Barry M. Farr, MD, MSc University of Virginia Health System Charlottesville, VA

Mechanisms Of Developing Antibiotic Resistance Random genetic mutation. Plasmid swapping during conjugation. Movement of transposons to plasmids/chromosomes. Transduction by bacteriophages. Transformation (acquisition of resistant genes from a recently killed cell and incorporation into a chromosome or plasmid). Binary fission (replication) can share any of the above.

Mechanisms Of Developing Antibiotic Resistance Natural Selection Darwin C. On the Origin of Species by Means of Natural Selection, London, 1859.

Univariate Analysis Of Antibiotic Exposure

VRE Incidence Week Hospital Ward 1 2 3 4 6th Floor ICU 0 0 0 0 Step-down Unit 0 0 0 0 5th Floor ICU 2 1 0 0 Step-down Unit 4 2 1 1 3rd Floor ICU 1 1 1 0 Step-down Unit 6 3 0 1 Byers KE, et al. ICHE 2001;22(3):140-147.

Transmission Of Individual Clones Of VRE Boyce, J Cin Micro 1994;32:1148. Dembry, SHEA 1994 Abstract #28. Edmond, Clin Infect Dis 1995;20:1126. Handwerger, Clin Infect Dis 1993;16:750. Livornese, Ann Int Med 1992;117:112. Montecalvo, Anti Ag Chemo 1994;38:1363. Rubin, Infect Cont Hosp Epi 1992;13:700.

MRSA Isolates From ICUs vs Non-ICUs ICU=intensive care unit Fridkin. Clin Chest Med. 1999;20(2):303.

Failure To Prevent MRSA Spread Thompson et al. found that despite isolation of patients known to have MRSA from clinical cultures, the prevalence of MRSA infection continued to increase. Thompson RL, Ann Intern Med 1982;97:309

Control of MRSA Using Active Surveillance Cultures and Contact Precautions Cases Date Incidence ( p < 0.002) and Prevalence (p < 0.001)

MRSA (which had been out of control for 2 MRSA (which had been out of control for 2.5 years) Was Completely Eradicated from the Hospital Within 1.5 years This was done with no antibiotic control effort of any kind.

Reservoir for the Spread of Antibiotic Resistant Pathogens Clinical Infections Colonized Patients

Prevalence of MRSA Colonization During the Outbreak

Follow-up After Control of MRSA Outbreak in NICU No MRSA in any patient during the next 10 years and about 100,000 patient-days. This suggests a low frequency of de novo development of methicillin resistance despite prolonged hospital stay and frequent antibiotic therapy in the NICU. It also suggests a very low rate of MRSA colonization among NICU workers and mothers in central Virginia.

Control of 2 MRSA NICU Outbreaks Using ASC and Barrier Precautions Without Antibiotic Control First outbreak in a 50-bed NICU controlled over several months 32 colonized over 5 weeks 5 colonized infants (16%) became infected and one died of MRSA BSI. 2nd outbreak of 14 colonized and 4 infected (29%) (with another death due to MRSA BSI) controlled in less than one month. Back NA, et al. ICHE 1996;17:227-231.

Haley RW et al, JID 1995;171:614-624.

Countries Controlling MRSA to < 1% of Nosocomial S Countries Controlling MRSA to < 1% of Nosocomial S. aureus Infections Using ASC and Barrier Precautions Denmark Netherlands Finland (Belgium has started and rate is falling)

Antimicrobial Resistance Surveillance in Staphylococcus aureus blood isolates, Denmark, 1960-1995 Methicillin 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 Penicillin Tetracycline Fusidic Acid Gentamicin Ciprofloxacin Erythromycin Staphylococcus aureus Antimicrobial Resistance Year Source: DANMAP Report, 1997.

Percentage of Nosocomial Enterococci Reported as Resistant to Vancomycin, by Year *National Nosocomial Infections Surveillance (NNIS) System Data, 1989-1999.

Byers KE et al. ICHE 2001;22:140-7.

Follow-up After Control of VRE in ICU Reaching 100% Prevalence Early in Outbreak Prevalence rapidly decreased to 0%. No VRE isolated from any patient in the ICU during the next year despite weekly cultures of all patients at risk and the lack of an antibiotic control program. This suggests a low frequency of de novo mutation to vancomycin resistance despite prolonged hospital stay and frequent antibiotic therapy.

Relationship Between Antibiotic Therapy and Development of VRE Culture Positivity “Antibiotics alone will not select for VRE if resistant bacteria are not already present or if a patient does not come into contact with them.” Murray BE. NEJM 2000;342:710-721.

Control of VRE with Active Surveillance Cultures and Contact Isolation in California Hospital

Muto CA, et al. IDSA 2001, abstract 210, p. 75. 40 Week 45 60 20 Muto CA, et al. IDSA 2001, abstract 210, p. 75.

VRE Prevalence in 30 Healthcare Facilities, Siouxland, 1997 vs 1999 Ostrowsky BE, et al., NEJM 2001;344:1427-1433.

MRSA BSI VRE BSI A B C D E F UVA Hospital No. of BSI in 1999 VRE and MRSA Bacteremias at Hospitals of Comparable Size and Complexity, 1999 Calfee DP, et al. SHEA 2001, abstract 127, p 66.

Control of VRE Using Active Surveillance Cultures and Contact Precautions Karanfil LV. ICHE 1992; 13: 195 Byers KE. ICAAC 1995 Boyce J. J Clin Micro 1994; 32: 1148 Rubin LG. ICHE 1992; 13: 700 Montecalvo M. AAC 1994; 38: 1363 Dembry L. ICHE 1996; 17: 2 Rupp ME. SHEA 1998; Abst. 54, p34 Malik RK. PIDJ 1999; 18: 352 Muto CA. SHEA 1998 Trick W. JID 1999; 180: 391 Jochimsen E. ICHE 1999; 20: 106 Calfee DP. SHEA 2000; Abst. P-T2-69, p217 Sohn A. SHEA 2000; Abst. S-Th-04, p261 Livornese LL. Ann Int Med 1992; 117: 112 Many studies have reported successful control of VRE using active identification and isolation of colonized patients.

STUDIES REPORTING FAILURE OF INFECTION CONTROL MEASURES TO CONTROL VRE # of Wards on which Active Surveillance Cultures were Used: Study: # Wards: % of Hospital Beds: 1 0 0% 2 1 <3% 3 2 <5% 4 4 ? Slaughter Ann Int Med 1996;125:448. Morris Ann Int Med 1995;123:250. Goetz, et al. AJIC 1998;26:558. Quayle, et al. CID 1996;23:1020.

Source of New VRE Cases in a Hospital with a High VRE Prevalence and Polyclonality Molecular epidemiologic analysis showed that establishment of endemicity had been mostly due to clonal spread with accumulation of new strains over time. Kim NJ et al. JID 1999;179:163.

Source of New VRE Cases in a Medical ICU with a High VRE Prevalence and Polyclonality The proportion of other patients with VRE was the most important risk factor for new patients becoming culture positive for VRE. In multivariable analysis, this was a more important predictor than other variables found to be significant in univariate analysis such as therapy with third generation cephalosporins. Bonten MJ et al. Arch Int Med 1998;158:1127.

Another Explanation of VRE Polyclonality Despite Documentation of Patient to Patient Spread Transposons (e.g., TN 5482) spread from Enterococcus to Enterococcus to chromosomes or plasmids by conjugation. de Lancastre, et al. Microbial Drug Resistance 1999;5:113.

Can Hand Hygiene/ Standard Precautions Control MRSA and VRE Infections (i.e., without using ASC and barrier precautions)? Hand hygiene rates in most hospitals have not changed since implementation of universal (standard) precautions. Pittet showed decrease in MRSA with increase in hand hygiene, but with much bigger increase in ASC and CP for colonized patients. Lancet 2000;356:1307-12. J Hosp Infect 2000;46:43-9. Larson reported significant 85% relative reduction in VRE but 44% drop in control hospital and no significant change in MRSA in same hospital with increase in hand hygiene. Behav Med 2000;26:14-22.

Can Hand Hygiene/ Standard Precautions Control MRSA and VRE Infections? Austin et al reported that 80% compliance with hand hygiene would result in relative reduction in VRE prevalence of about 25% (PNAS 1999;96:6908-13). Sebille et al reported that increasing hand hygiene compliance to 90% would only reduce MRSA prevalence by 33%. They recommended ASC and CP (ICHE 1997;18:84-92). Some have claimed that switching to triclosan handwash alone ended 2 MRSA NICU outbreaks, but both used multiple measures and reported continuing “all IC measures” (e.g., one used weekly ASC and and the other used gowns, gloves, cohorting and bathing of every neonate with triclosan). Webster J et al, J Paed Child Health 1994;30:59-64. Zafar AB et al, AJIC 1995;3:200-8. .

Rates of MRSA Transmission Jernigan, et al. Am J Epi 1996;143:496-504.

Conditional Logistic Regression Analysis Variable OR P Proximity to unisolated 2.04* 0.0014 VRE patients History of major trauma 9.27 0.020 Metronidazole therapy 3.04 0.040 * Per exposure-unit Byers KE et al. ICHE 2001;22:140-7.

MRSA Isolates From ICUs vs Non-ICUs SP UP ICU=intensive care unit Fridkin. Clin Chest Med. 1999;20(2):303.

Percentage of Nosocomial Enterococci Reported as Resistant to Vancomycin, by Year SP UP *National Nosocomial Infections Surveillance (NNIS) System Data, 1989-1999.

ISOLATION GOWNS PREVENT HCWs FROM CONTAMINATING THEIR CLOTHES/HANDS 14 (40%) of 35 HCWs’ gowns were culture (+) for MRSA and ARE on exiting room (2-200 colonies recovered). Clothing underneath was culture (-). 11 (69%) of 16 HCWs wearing freshly laundered white coats had detectable contamination. 3 of 11 developed (+) hand cultures after touching the white coat. Boyce, et al. SHEA 1998, Abstract S74.

CONTAMINATION OF GOWNS, GLOVES AND STETHOSCOPES Two thirds of examinations of VRE patients resulted in VRE contamination of gown, gloves and/or stethoscopes. Same rate of contamination whether the patient was infected or merely colonized. Zachary KC et al. 4th Decennial Conference on Nosocomial Infections, Atlanta, p. 75.

Environmental MRSA Contamination 70% of rooms had environmental contamination when the patient was colonized or infected and 42% of nurses’ gloves were contaminated after touching environmental surfaces without touching patient.1 7% of stethoscopes were contaminated with MRSA2 Wiping with 70% isopropyl alcohol significantly reduced colony counts on stethoscopes (p < 0.02).3 Contaminated surfaces include patient’s gowns, floor, bed linens, blood pressure cuffs, overbed tables, stethoscopes, etc.1 1Boyce. Infect Control Hosp Epidemiol. 1997;18:622. 2 Cohen. Fam Pract. 1997;14:446 3 Marinella. Arch Intern Med. 1997;157:786.

Rates of Persistent Environmental VRE Contamination Conventional 60/376 = 15.9% Bucket 0/135 = 0% Chi Square = 25.7 p < 0.001 Byers KE et al. ICHE 1998;19:261-4.

Excess Cost of MRSA Infection MRSA infections cost significantly more than MSSA infections. Engelmann J et al, ICAAC 2001 abst. K-2056, p. 441. Cosgrove SE et al, ICAAC 2001 abst. K-1221, p. 415. Abramson, ICHE 1999;20:408. Wakefield, AJIC 1988;16:185-192. Cheng, J Hosp Infect 1988;12:91-101.

Comparison of Primary MSSA and MRSA Nosocomial Bloodstream Infections Abramson, ICHE 1999;20:408.

Costs Of VRE Bacteremia VRE bacteremia associated with significant increases in length of stay (p=0.004), and hospital costs (more than $27,000 per episode, p=0.04).1 VRE BSI associated with 19-day increase in length of stay (p<0.001), and increased hospital costs ($79,589 per episode, p<0.001).2 1) Stosor V, et al., Arch Int Med 1998;158:522. 2) Song X, et al, 37th IDSA, 1999, abstract 500, p 126.

Studies Reporting Cost Benefit of Surveillance Cultures and Contact Precautions for Controlling MRSA & VRE Chaix, et al. JAMA 1999;282:1745. Jernigan JA, et al. ICHE 1995;16:686. Montecalvo MA, et al. ICHE 2001 July;22:437-42. Karchmer TB et al, J Hosp Infect. In press. Muto CA et al, SHEA 1999 abstract 74, p. 44. Calfee DP, et al. SHEA 2001, abstract 127, p 66.

Attributable Mortality of MRSA Bacteremia Association with death was almost two-fold higher for MRSA bloodstream infections than for MSSA BSI (OR=1.9, 95% CI, 1.5,2.4, p < 0.001) after adjustment for severity of illness in a recent meta-analysis. Cosgrove. SHEA 2001. Abstract #96.

Mortality with S. aureus Pneumonia MRSA 54.5% MSSA 2.6% (RR=20.7, 95% CI=2.8-154) Rello, Am J Resp Crit Care Med 1994;150:1545.

Factors Independently Associated with Mortality Among Patients with Pneumonia due to S. aureus Gonzalez, et al. CID 1999;29:1171.

Attributable Morbidity and Mortality Of VRE Bacteremia Compared to VSE, available data suggest that VRE bacteremia has: higher rates of recurrence 16.9% vs. 3.7% p<0.0001 higher crude case fatality rates RR=2.57 [95%CI= 2.27-2.91] higher mortality due to bacteremia per se RR=1.79 [95%CI= 1.28-2.50] Salgado, CD. SHEA 2002, Abstract #113.

Salgado, CD. SHEA 2002, Abstract #113. Studies Comparing VRE and VSE Bacteremic Patients Matched for Severity of Illness   *Patients matched by APACHE II Score **Patients matched by other severity of illness score Salgado, CD. SHEA 2002, Abstract #113.

Salgado, CD. SHEA 2002, Abstract #113. Multivariable Analyses of Mortality Risks for Enterococcal Bacteremia Of 10 multivariate analyses of patients with enterococcal bacteremia, 3 reported no elevated risk of death associated with vancomycin resistance 3 reported an elevated risk of death with vancomycin resistance that was not statistically significant but with wide 95% CIs 4 reported a significantly elevated risk of death (with similar ORs to 3 other studies). These 4 studies tended to be larger and have greater statistical power than the negative studies. Salgado, CD. SHEA 2002, Abstract #113.

MRSA Isolates From ICUs vs Non-ICUs ICU=intensive care unit Fridkin. Clin Chest Med. 1999;20(2):303.

Antimicrobial Resistance Surveillance in Staphylococcus aureus blood isolates, Denmark, 1960-1995 Methicillin 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 Penicillin Tetracycline Fusidic Acid Gentamicin Ciprofloxacin Erythromycin Staphylococcus aureus Antimicrobial Resistance Year Source: DANMAP Report, 1997.

Antimicrobial Resistance Surveillance in Staphylococcus aureus blood isolates, Denmark, 1960-1995 Methicillin 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 Penicillin Tetracycline Fusidic Acid Gentamicin Ciprofloxacin Erythromycin Staphylococcus aureus Antimicrobial Resistance Year Source: DANMAP Report, 1997.