Controlling MRSA and VRE: Is It Important to Identify the Reservoir? Barry M. Farr, MD, MSc Hospital Epidemiologist The William S. Jordan Jr. Professor of Medicine and Epidemiology University of Virginia Health System Charlottesville, VA Hosted by Paul Webber email@example.com A Webber Training Teleclass www.webbertraining.com
THE INFECTIOUS DISEASE PROCESS 1. Etiologic agent 2. Reservoir 3. Portal of exit 4.Method of transmission 5. Portal of entry 6. Susceptible host
Criteria for Causal Inference • Strength of association • 2. Consistency of evidence • 3.Temporal relationship • 4. Biological gradient • 5. Reversibility • 6. Specificity • 7. Coherence of evidence Hill AB. A Short Textbook of Medical Statistics (11th ed.), p. 273. London, UK: Unibooks. 1984.
Rapid Increase in the Prevalence of Penicillin-resistant Staphylococcus aureus, Hammersmith Hospital, London 1941 <1% 1946 13% 1947 38% 1948 59%
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.
Prevalence of Antibiotic Therapy in U.S. Hospitals In Recent Surveys • Almost half of all patients • Almost all ICU patients
VRE Incidence WeekHospital 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 IndividualClones 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 Fridkin. Clin Chest Med. 1999;20(2):303. ICU=intensive care unit
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 2.5 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 Recognized by results of Clinical Microbiology Cultures Colonized Patients
CDC Guideline for Isolation Precautions • The CDC guideline for isolation precautions recommends contact isolation for “patients known or suspected to be colonized or infected with epidemiologically important” antibiotic-resistant microorganisms. Garner, et al. ICHE 1996;17:53
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.
Studies Reporting Control of MRSA Using ASC & CP Haley RW, et al. J Infect Dis 1995; 171:614-624. Jernigan JA, et al. Am J Epidemiol 1996; 143:496-504. Salmenlinna S, et al. Euro J Clin Micro & Infect Dis 2000; 19:101-107. Vriens MR, et al, ICHE 2002; 23:491-494. Thompson R, et al. Ann Intern Med 1982; 97:309-317. Jernigan J et al, ICHE 1995; 16:686-696. Jans B, et al, ICHE 2000; 21:419. Harbarth S, et al. J Hosp Infect 2000; 46:43-49. Back NA, et al, ICHE 1996; 17:227-231. Calfee DP, et al, ICHE 2002; 23:407-410.
Studies Reporting Control of MRSA Using ASC & CP Chaix C, et al. JAMA 1999; 282:1745-51. Law MR, et al. Epidemiol Infect 1988; 101:623-629. Murray-Leisure KA, et al, ICHE 1990; 11:343-350. Nicolle LE, et al ICHE 1999; 20:202 -205. Cantey J, et al. SHEA. 2002; Abstract 36:49. Croyle K, et al, SHEA. 2002; Abstract 35:49. Kotilainen P, et al. Arch Intern Med 2001; 161:859-863. Nouer A, et al ICAAC 2002; K-97: 97. Horcajada J, et al ICAAC 2002:K-98. Gerard M, et al ICAAC 2002:K-99. Verhoef J, et al. Eur J Clin Micro Infect Dis 1999; 18:461-466. Cooper CL et al, ICHE 2002;23:483-484.
Publications From Northern European Countries Reporting Control of MRSA To A Very Low Prevalence Using ASC & CP Verhoef J, et al. Eur J Clin Micro Infect Dis 1999; 18:461-466. Salmenlinna S, et al. Euro J Clin Micro & Infect Dis 2000; 19:101-107. Bager F. DANMAP 98. www.svs.dk/dk/z/Danmap%201998.pd 1999. Vriens MR, et al, ICHE 2002; 23:491-494.
100% 90% 80% Penicillin 70% 60% Tetracycline 50% Methicillin 40% Fusidic Acid Gentamicin Ciprofloxacin 30% 20% 10% Erythromycin 0% 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 Antimicrobial Resistance Surveillance in Staphylococcus aureus blood isolates, Denmark, 1960-1995 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.
Follow-up After Control of VRE in ICU Reaching 100% Prevalence Early in Outbreak Prevalence rapidlydecreased 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
COST-EFFECTIVENESS OF PREVENTING VRE INFECTIONS • Expanded control measures including active surveillance cultures and contact isolation to prevent spread of VRE resulted in hospital savings of $189,318 per year1 (despite a high prevalence and polyclonality2 of the VRE isolates). 1) Montecalvo MA, et al.ICHE 2001 July;22:437-42. 2) Montecalvo MA, et al. ICHE 1995 Dec;16:680-85.
40 Week 45 60 0 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.
VRE and MRSA Bacteremias at Hospitals of Comparable Size and Complexity, 1999 MRSA BSI VRE BSI No. of BSI in 1999 A B C D E F UVA Hospital Calfee DP,et al.ICHE 2002;23:407-410.
Studies Reporting Control of VRE Using ASC & CP Boyce JM, et al, ICHE 1995; 16:634-637. Boyce JM, et al. J Clin Microbiol 1994; 32:1148-1153. Livornese LL, et al. Ann Intern Med 1992; 117:112-116. Byers KE, et al, ICHE 2001; 22:140-147. Ostrowsky BE, et al. N Engl J Med 2001; 344:1427-1433. Calfee DP, et al, ICHE 2002; 23:407-410. Karanfil LV, et al, ICHE 1992; 13:195-200. Montecalvo MA, et al. Antimicrob Agents Chemother 1994; 38:1363-1367. Dembry L, et al, ICHE 1996; 17:286-292. Rupp ME, et al, ICHE 2001; 22:301-303.
Studies Reporting Control of VRE Using ASC & CP Malik RK, et al. Pediatric Infect Dis J 1999; 18:352-356. Muto CA, et al, SHEA 1998; Abstract no 76:38. Rubin LG, et al, ICHE 1992; 13:700-705. Jochimsen E, et al, ICHE 1999; 20:106-109. Golan Y, et al, IDSA 2001; 209:75. Price CS, et al, IDSA 2001; 212:75. Siddiqui AH, et al. AJIC 2002; 30:40-43. Calfee DP, et al, IDSA. 2000; Abstract: 21:44. Muto CA, et al, ICHE 2002; 23:429-435. Christiansen K, et al, ICAAC 2002, abstract K-660, page 317. Muto CA, et al, abstract 164, SHEA 2002, page 80.
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 establishmentof 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.
VRE Polyclonality Due to Spread of Transposons (i.e., despite patient to patient spread) Transposons (e.g., TN 5482) spread from Enterococcus to Enterococcus to chromosomes or plasmids by conjugation. de Lencastre H, et al.Microbial Drug Resistance 1999;5:113.
100% 90% 80% Penicillin 70% 60% Tetracycline 50% Methicillin 40% Fusidic Acid Gentamicin Ciprofloxacin 30% 20% 10% Erythromycin 0% 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 Could Hand Hygiene Alone Control MRSA Like This? Staphylococcus aureus Antimicrobial Resistance Year Source: DANMAP Report, 1997.
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, (Lancet 2000;356:1307-12.) but with much bigger increase in ASC and CP for colonized patients. (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 intervention hospital despite 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 a relative reduction in VRE prevalence of about 25% (PNAS 1999;96:6908-13). Much better control was found with ASC and cohort isolation. • 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. .
Can Hand Hygiene/ Standard Precautions Control MRSA and VRE Infections? • Vernon reported decreases in MRSA and VRE in a LTCF following a hand hygiene campaign with alcohol handrub (Vernon MO et al IDSA 2001 abstract 249, p.82) but not in the the other 2 healthcare facilities involved in the campaign. (Vernon MO et al ICAAC 2001 abstract K-1331, p. 424.) • Gundlapalli reported increased VRE (not statistically significant) after switching from ASC & CP to SP in an ICU with a “multidimensional campaign to encourage strict adherence” for 7 months but abstract did not comment on control measures in the rest of the tertiary care hospital. (Gundlapalli AV et al IDSA 2001abstract 250, p. 82. ) • Schultz reported an insignificant decline in VRE and no change in MRSA or C. difficile after one year of a hand hygiene campaign emphasizing use of an alcohol handrub. (Schultz ICAAC 2002, K-1099, p. 323.) .
Rates of MRSA Transmission Jernigan, et al. Am J Epi 1996;143:496-504.
Rates of Clonal MRSA Transmission Unisolated Isolated Transmissions 38 * 1^ Assumed person days at risk X X *= # acquiring MRSA clone from 3 unisolated ICU patients (i.e., 23 patients and 15 HCWs) ^= # acquiring MRSA clone from 3 isolated ICU patients RR=38.0, 95% CI=6.4-1539.9, p<10-6 Vriens MR, et al, ICHE 2002; 23:491-494.
Conditional Logistic Regression Analysis VariableORP 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 Fridkin. Clin Chest Med. 1999;20(2):303. ICU=intensive care unit