Resistant Organisms and Resistant Organisms and Nosocomial Nosocomial Infections: MRSA Infections: MRSA and CRBSI and CRBSI Jim Pile, MD, FACP Jim Pile, MD, FACP Divisions of Hospital Medicine Divisions of Hospital Medicine and Infectious Diseases and Infectious Diseases CWRU/MetroHealth Medical Center CWRU/MetroHealth Medical Center
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Resistant Organisms and Nosocomial Infections: MRSA and CRBSI Jim Pile, MD, FACP Divisions of Hospital Medicine and Infectious Diseases CWRU/MetroHealth.
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Resistant Organisms and Nosocomial Resistant Organisms and Nosocomial Infections: MRSA and CRBSIInfections: MRSA and CRBSI
Jim Pile, MD, FACPJim Pile, MD, FACP
Divisions of Hospital Medicine and Divisions of Hospital Medicine and Infectious DiseasesInfectious Diseases
CWRU/MetroHealth Medical CenterCWRU/MetroHealth Medical Center
A 35 Year Old Man . . . .A 35 Year Old Man . . . .
Is admitted with a several day history of a "boil" Is admitted with a several day history of a "boil" on his right upper arm. The area has become on his right upper arm. The area has become increasingly tender, and "feels like it has pus in it." increasingly tender, and "feels like it has pus in it." He noted chills and subjective fever last night, and He noted chills and subjective fever last night, and states he has had 2 similar episodes in the past 6 states he has had 2 similar episodes in the past 6 months. On exam, he has a T of 38.0months. On exam, he has a T of 38.0º C, with BP º C, with BP of 138/84, HR 94. A 6 cm abscess is present on of 138/84, HR 94. A 6 cm abscess is present on the lateral aspect of his R upper arm, with modest the lateral aspect of his R upper arm, with modest surrounding cellulitis. Exam is o/w normal.surrounding cellulitis. Exam is o/w normal.
A 35 Year Old Man . . . .A 35 Year Old Man . . . .
He reports throat swelling with vancomycin, and He reports throat swelling with vancomycin, and hives with sulfa drugshives with sulfa drugs
Does he need antibiotic therapy, or will drainage Does he need antibiotic therapy, or will drainage suffice?suffice?
If "yes," which antibiotic will you choose?If "yes," which antibiotic will you choose?
Should he be cultured for MRSA colonization, and Should he be cultured for MRSA colonization, and if + should decolonization be attempted?if + should decolonization be attempted?
MRSAMRSA
Arose from single cloneArose from single clone
Carry mecA gene, located on SCCCarry mecA gene, located on SCC
5 types of SCCmec, which code for antibiotic 5 types of SCCmec, which code for antibiotic resistanceresistance
Spread of SCCmec from MRSA to MSSA isolates Spread of SCCmec from MRSA to MSSA isolates well-documentedwell-documented
> 50% of > 50% of Staph aureusStaph aureus isolates from U.S. hospitals isolates from U.S. hospitals
Moran et al, NEJM 2006;355:666Moran et al, NEJM 2006;355:666
Changing Epidemiology of Changing Epidemiology of Nosocomial MRSA InfectionNosocomial MRSA Infection
Harbor-UCLA study found Harbor-UCLA study found CA-MRSA made up CA-MRSA made up increasing proportion of increasing proportion of nosocomial MRSA infxsnosocomial MRSA infxs
Stroger/Cook County: % of Stroger/Cook County: % of nosocomial MRSA BSI due nosocomial MRSA BSI due to CA-MRSA rose from 24% to CA-MRSA rose from 24% in 2000-03 to 49% in 2003-06in 2000-03 to 49% in 2003-06
Pooled hazard ratio of 1.93 Pooled hazard ratio of 1.93 for MRSAfor MRSA
Appeared to hold up even Appeared to hold up even when co-morbidities and when co-morbidities and severity of underlying severity of underlying illness controlled forillness controlled for
Cosgrove, CID 2003;36:53Cosgrove, CID 2003;36:53
CA-MRSA vs CA-MSSA: Not CA-MRSA vs CA-MSSA: Not So Much?So Much?
Single-center Taiwanese study examined outcome Single-center Taiwanese study examined outcome in pts admitted with CA-MRSA vs CA-MSSA in pts admitted with CA-MRSA vs CA-MSSA bacteremia 2001-2006bacteremia 2001-2006
More SSTI and pneumonia in MRSA group, more More SSTI and pneumonia in MRSA group, more endovascular infection in MSSAendovascular infection in MSSA
30-day survival: 90% (MRSA) vs 87% (MSSA); 30-day survival: 90% (MRSA) vs 87% (MSSA); p=0.62p=0.62
Wang, CID 2008;46:799Wang, CID 2008;46:799
Does Our Patient Require Does Our Patient Require Antibiotic Therapy?Antibiotic Therapy?
Several studies have suggested that CA-MRSA Several studies have suggested that CA-MRSA skin infections may not require abts after skin infections may not require abts after adequate drainage (all small/flawed)adequate drainage (all small/flawed)
492 patients, 531 episodes of CA-MRSA SSTIs492 patients, 531 episodes of CA-MRSA SSTIs
41% received inactive antibiotics41% received inactive antibiotics
8.5% treatment failure: 5% with active abt, 13% 8.5% treatment failure: 5% with active abt, 13% with inactive (OR 2.80, p=.001)with inactive (OR 2.80, p=.001)
Ruhe, CID 2007;44:777Ruhe, CID 2007;44:777
MRSA ColonizationMRSA Colonization
Colonization typically precedes infectionColonization typically precedes infection
Is eradication of colonization possible?Is eradication of colonization possible?
Does eradication of colonized state prevent infection?Does eradication of colonized state prevent infection?
Mupirocin + chlorhexidine + rifampin + doxycycline vs Mupirocin + chlorhexidine + rifampin + doxycycline vs no treatmentno treatment
-74% vs 32% MRSA-free at 3 months-74% vs 32% MRSA-free at 3 months
-54% MRSA-free at 8 months-54% MRSA-free at 8 months
Simor, CID 2007;44:178Simor, CID 2007;44:178
Should Decolonization be Should Decolonization be Attempted in Our Patient?Attempted in Our Patient?
Criteria for attempting decolonization not well Criteria for attempting decolonization not well defineddefined
Importance of CA-MRSA at extranasal sites Importance of CA-MRSA at extranasal sites
Vancomycin: A Suboptimal Vancomycin: A Suboptimal Agent for Agent for Staph aureusStaph aureus
Recent case-control study of MSSA bacteremia: Recent case-control study of MSSA bacteremia: mortality 37% with vanco, 11% with B-lactams (p<0.01)mortality 37% with vanco, 11% with B-lactams (p<0.01)
54 cases of MSSA bacteremic pneumonia treated with 54 cases of MSSA bacteremic pneumonia treated with vancomycin or cloxacillin: mortality 47% vs 0%vancomycin or cloxacillin: mortality 47% vs 0%
123 ESRD pts with MSSA bacteremia treated with vanco 123 ESRD pts with MSSA bacteremia treated with vanco or cefazolin: 31% vs 13% failed treatment, OR 3.5or cefazolin: 31% vs 13% failed treatment, OR 3.5
Kim, AAC 2008;52:192; Gonzalez CID 1999;29:1171; Stryjewski, CID Kim, AAC 2008;52:192; Gonzalez CID 1999;29:1171; Stryjewski, CID 2007;44:1902007;44:190
Time-Kill Curves for MSSA (Time-Kill Curves for MSSA (from from
Mounting Concerns Over Mounting Concerns Over Vancomycin EffectivenessVancomycin Effectiveness
Growing sense that efficacy against MRSA may be Growing sense that efficacy against MRSA may be lesseninglessening
Emergence of VISA, VRSAEmergence of VISA, VRSA
--VISA: MIC 4-8 mcg/ml; VRSA: --VISA: MIC 4-8 mcg/ml; VRSA: ≥ 16 mcg/ml≥ 16 mcg/ml
Phenomenon of heteroresistance (hVISA) a much Phenomenon of heteroresistance (hVISA) a much bigger problem at present bigger problem at present
----Heterogeneous population of MRSA, with a Heterogeneous population of MRSA, with a sub-sub-
population unresponsive to vancomycin despite population unresponsive to vancomycin despite reported reported sensitivitysensitivity
MIC UncertaintiesMIC Uncertainties
Based on mounting data, MRSA susceptibility Based on mounting data, MRSA susceptibility breakpoint for vanco changed from breakpoint for vanco changed from ≤ 4 mcg/ml to ≤ 4 mcg/ml to ≤ 2 mcg/ml in 2006≤ 2 mcg/ml in 2006
Many labs have difficulty with MRSA MICsMany labs have difficulty with MRSA MICs
≤ ≤ 2 mcg/ml, however, still does not confirm true 2 mcg/ml, however, still does not confirm true susceptibilitysusceptibility
15% of strains with very low MIC by reliable 15% of strains with very low MIC by reliable testing still vanco tolerant!testing still vanco tolerant!
MRSA MIC vs Vancomycin MRSA MIC vs Vancomycin Failure Rate (Failure Rate (Stevens, CID 2006;42:S51Stevens, CID 2006;42:S51))
agragr Polymorphism: Still More Polymorphism: Still More Trouble?Trouble?
agr agr gene cluster regulates gene cluster regulates a variety of key virulence a variety of key virulence and metabolic pathwaysand metabolic pathways
Down-regulated function Down-regulated function appears to confer tolerance appears to confer tolerance to vancomycin; MIC may to vancomycin; MIC may still be very lowstill be very low
Have low vanco levels in Have low vanco levels in past driven emergence?past driven emergence?
Evidence suggests that a vancomycin trough of 4-5X Evidence suggests that a vancomycin trough of 4-5X the MIC may be optimal for serious MRSA infectionsthe MIC may be optimal for serious MRSA infections
Penetration of vancomycin into lung only 20-30% of Penetration of vancomycin into lung only 20-30% of that achieved in serumthat achieved in serum
It may be difficult to achieve adequate It may be difficult to achieve adequate concentrations of vancomycin in the lung, concentrations of vancomycin in the lung, particularly if the MIC of the organism is relatively particularly if the MIC of the organism is relatively higherhigher
Will High-dose Vancomycin Will High-dose Vancomycin Overcome These Concerns?Overcome These Concerns?
95 pts with nosocomial MRSA infections (low vs high 95 pts with nosocomial MRSA infections (low vs high MIC: ie, MIC: ie, ≤ 1 mcg/ml or > 1 mcg/ml)≤ 1 mcg/ml or > 1 mcg/ml)
Even with achievement of high trough levels, Even with achievement of high trough levels, outcome worse in high MIC group: 62% vs 85% outcome worse in high MIC group: 62% vs 85% response (p=.02)response (p=.02)
Uncertain whether benefit associated with high Uncertain whether benefit associated with high troughstroughs Hidayat, Arch Intern Med 2006;166:2138Hidayat, Arch Intern Med 2006;166:2138
"There is an antibiotic called mud"There is an antibiotic called mud
That's proving to be quite a dud.That's proving to be quite a dud.
Its provenance is jungleIts provenance is jungle
Its use is a bungleIts use is a bungle
It just won't get rid of your crud"It just won't get rid of your crud"
-Stan Deresinski, MD-Stan Deresinski, MD
CID 2007;44:1543CID 2007;44:1543
Trimethoprim/Sulfa Trimethoprim/Sulfa and MRSAand MRSA
1992 study of 101 IVDU pts with 1992 study of 101 IVDU pts with serious Staph aureus infxs: serious Staph aureus infxs: 86% cured with TMP/SMX, 98% 86% cured with TMP/SMX, 98% (!) with vancomycin(!) with vancomycin
No failures in either group with No failures in either group with MRSA (47%). Authors MRSA (47%). Authors concluded vanco superior, but concluded vanco superior, but TMP/SMX a valuable alternativeTMP/SMX a valuable alternative
Markowitz, Ann Int Med 1992;117-Markowitz, Ann Int Med 1992;117-390; Proctor, CID 2008;46:584390; Proctor, CID 2008;46:584
Tetracycline and Clindamycin Tetracycline and Clindamycin Treatment of MRSATreatment of MRSA
Retrospective study of 24 Retrospective study of 24 pts with MRSA infxs pts with MRSA infxs treated with long-acting treated with long-acting tetracyclines: 83% cured tetracyclines: 83% cured
Review of world literature: Review of world literature: 85% of 85 pts treated with 85% of 85 pts treated with TCNs responded wellTCNs responded well
Ruhe, CID 2005;40:1429Ruhe, CID 2005;40:1429
Clindamycin: most MRSA Clindamycin: most MRSA strains remain sensitivestrains remain sensitive
Some data suggest Some data suggest efficacy in children with efficacy in children with serious MRSA infxserious MRSA infx
Very limited data in Very limited data in adults adults
DaptomycinDaptomycin
Cyclic lipopeptide, rapidly bactericidal against Cyclic lipopeptide, rapidly bactericidal against S. S. aureusaureus
2006 study of daptomycin vs standard therapy for 2006 study of daptomycin vs standard therapy for MRSA, MSSA bacteremiaMRSA, MSSA bacteremia
-Daptomycin "not inferior" to standard treatment-Daptomycin "not inferior" to standard treatment
2004 cSSTI trial, dapto vs standard tx: 2004 cSSTI trial, dapto vs standard tx:
-83% vs 84% cure-83% vs 84% cure
Daptomycin NOT appropriate for pneumonia Daptomycin NOT appropriate for pneumonia Fowler, NEJM 2006;355:653Fowler, NEJM 2006;355:653 Arbeit, CID 2004;38:1673Arbeit, CID 2004;38:1673
Linezolid vs Vancomycin in Linezolid vs Vancomycin in Nosocomial PneumoniaNosocomial Pneumonia
RCT comparing linezolid + aztreonam to vanco + RCT comparing linezolid + aztreonam to vanco + aztreonam for nosocomial pneumoniaaztreonam for nosocomial pneumonia
Continuation study: 345 patients evaluable, Continuation study: 345 patients evaluable, clinical efficacy/mortality again equivalent (cure clinical efficacy/mortality again equivalent (cure in 68% vs 65%; mortality 20% both arms)in 68% vs 65%; mortality 20% both arms)
Wunderink, RG. Linezolid vs vancomycin: Wunderink, RG. Linezolid vs vancomycin: analysis of 2 double-blind studies of patients analysis of 2 double-blind studies of patients with MRSA nosocomial pneumonia. Chest with MRSA nosocomial pneumonia. Chest 2003;124:17892003;124:1789
The epidemiology of MRSA continues to evolve, The epidemiology of MRSA continues to evolve, with CA-MRSA moving into the hospital with CA-MRSA moving into the hospital
Most CA-MRSA strains remain sensitive to Most CA-MRSA strains remain sensitive to multiple antibiotics--for the momentmultiple antibiotics--for the moment
Vancomycin MAY still be the drug of choice for Vancomycin MAY still be the drug of choice for serious MRSA infections, but leaves much to be serious MRSA infections, but leaves much to be desireddesired
Multiple alternatives exist, with more comingMultiple alternatives exist, with more coming
CRBSI: Diagnosis, Prevention CRBSI: Diagnosis, Prevention and Managementand Management
A 54 Year Old Woman with an A 54 Year Old Woman with an Entero-cutaneous Fistula . . . .Entero-cutaneous Fistula . . . .
After colo-rectal surgery and receiving TPN via After colo-rectal surgery and receiving TPN via a Hickman catheter presents with 2 days of a Hickman catheter presents with 2 days of fever to 102fever to 102° F and no other symptoms. Her T ° F and no other symptoms. Her T on presentation is 38.8° C, her BP/HR are on presentation is 38.8° C, her BP/HR are essentially normal, and her catheter exit site essentially normal, and her catheter exit site and tunnel are not inflamed. The remainder of and tunnel are not inflamed. The remainder of her physical exam is unrevealing.her physical exam is unrevealing.
A 54 y.o. with an ECF . . . .A 54 y.o. with an ECF . . . .
Should the catheter be removed on arrival?Should the catheter be removed on arrival?
If not, how will you decide whether it is the If not, how will you decide whether it is the culprit?culprit?
If you decide the catheter is infected, will the If you decide the catheter is infected, will the offending pathogen influence your decision to offending pathogen influence your decision to remove it?remove it?
If the catheter is retained, how will you treat the If the catheter is retained, how will you treat the infection?infection?
Scope of the ProblemScope of the Problem
> 5 million catheter-related infxs in US annually> 5 million catheter-related infxs in US annually
? 200K infections? 200K infections
80K CRBSI in U.S. ICUs, estimated 28,000 80K CRBSI in U.S. ICUs, estimated 28,000 deathsdeaths
Frequently not straightforwardFrequently not straightforward
Exit site inflammation: relatively specific, but Exit site inflammation: relatively specific, but very insensitivevery insensitive
Catheters frequently not the culprit in pts with Catheters frequently not the culprit in pts with unexplained fever (and may not be source of unexplained fever (and may not be source of bacteremia)bacteremia)
How can non-infected CVCs be distinguished?How can non-infected CVCs be distinguished?
Both expensive and laboriousBoth expensive and laborious
Safdar, Ann Intern Med 2005;142:451Safdar, Ann Intern Med 2005;142:451
Differential Time to PositivityDifferential Time to Positivity
Blood cultures obtained Blood cultures obtained simultaneouslysimultaneously from CVC and from CVC and peripherallyperipherally
CVC culture reported + at least 2 hours before peripheral CVC culture reported + at least 2 hours before peripheral considered diagnostic for CRBSIconsidered diagnostic for CRBSI
Sens/specif 89%/87% for short-term catheters; 90%/72% Sens/specif 89%/87% for short-term catheters; 90%/72% for tunneled cathetersfor tunneled catheters
Simple and widely availableSimple and widely available
More cost-effective than quantitative techniquesMore cost-effective than quantitative techniques
Mermel CID 2001;32:1249; Safdar Ann Intern Med 2005;142:451Mermel CID 2001;32:1249; Safdar Ann Intern Med 2005;142:451
Use subclavian vein Use subclavian vein when possiblewhen possible
MMWR 2002;51/RR-10MMWR 2002;51/RR-10
MHA Keystone ICU ProjectMHA Keystone ICU Project
103 ICUs in Michigan, 375K CVC days103 ICUs in Michigan, 375K CVC days
Comprehensive unit-based education, daily goals sheet, Comprehensive unit-based education, daily goals sheet, and VAP intervention as welland VAP intervention as well
Included 5 key measures: hand hygiene, full sterile Included 5 key measures: hand hygiene, full sterile barriers, chlorhexidine use, avoidance of femoral site, barriers, chlorhexidine use, avoidance of femoral site, removing unnecessary CVCsremoving unnecessary CVCs
Central line carts created, nurses empowered, checklists Central line carts created, nurses empowered, checklists used to increase complianceused to increase compliance
Significant reduction in Significant reduction in rate of CRBSI in quarter rate of CRBSI in quarter of implementationof implementation
Results sustained over Results sustained over duration of studyduration of study
CRBSI fell from mean of CRBSI fell from mean of 7.7 to 1.4 infections per 7.7 to 1.4 infections per catheter daycatheter day
"The structure of the intervention involved daily "The structure of the intervention involved daily commitment to a culture of safety . . . . We can no commitment to a culture of safety . . . . We can no longer accept the variations in safety culture, longer accept the variations in safety culture, behavior, or systems of practice that have plagued behavior, or systems of practice that have plagued medical care for decades. Imagine the effect if all medical care for decades. Imagine the effect if all 6000 acute care hospitals in the US were to show a 6000 acute care hospitals in the US were to show a similar commitment and discipline."similar commitment and discipline."
CDC: "consider" use of CDC: "consider" use of impregnated catheter impregnated catheter when expected to be in when expected to be in place > 5 daysplace > 5 days
Failure appears to frequently relate to inability to kill Failure appears to frequently relate to inability to kill organisms in luminal biofilmorganisms in luminal biofilm
Antibiotic concentration may need to be 100-1000X Antibiotic concentration may need to be 100-1000X greater to kill bacteria in biofilmgreater to kill bacteria in biofilm
ALT: 2-5 cc of antibiotic solution instilled into ALT: 2-5 cc of antibiotic solution instilled into lumen(s) and "locked"lumen(s) and "locked"
83% cure rate vs 67% with conventional therapy only 83% cure rate vs 67% with conventional therapy only
Mermel CID 2001;32:1249Mermel CID 2001;32:1249
Coagulase Negative StaphCoagulase Negative Staph
Leading cause of CRBSI in most seriesLeading cause of CRBSI in most series
Up to 80% of catheters salvageableUp to 80% of catheters salvageable
If catheter retained: 7 days systemic therapy, If catheter retained: 7 days systemic therapy, 10-14 days lock therapy (ALT)10-14 days lock therapy (ALT)
Catheter removed: 5-7 days systemic therapyCatheter removed: 5-7 days systemic therapy
Recent study reported cure in 13/15 HD catheter infxs Recent study reported cure in 13/15 HD catheter infxs (87%) with systemic + lock tx(87%) with systemic + lock tx
"Tough" pathogens ("Tough" pathogens (S. maltophilia, B. cepacia, S. maltophilia, B. cepacia, Acinetobacter, Acinetobacter, non-non-aeruginosa Pseudomonasaeruginosa Pseudomonas) appear ) appear less likely to respondless likely to respond
Catheter removed: 7-14 days systemic abtsCatheter removed: 7-14 days systemic abts
Catheter retained: 14 days systemic + ALT txCatheter retained: 14 days systemic + ALT tx
Poole, Nephrol Dial Transplant 2004;19:1237; Raad Lancet ID 2007;7:645;Poole, Nephrol Dial Transplant 2004;19:1237; Raad Lancet ID 2007;7:645;
Mermel CID 2001;32:1249Mermel CID 2001;32:1249
Candida sppCandida spp
Multiple prospective studies support worse Multiple prospective studies support worse outcome with attempted CVC salvageoutcome with attempted CVC salvage
70% failure rate even with systemic + lock tx70% failure rate even with systemic + lock tx
IDSA guidelines suggest amphotericin B for IDSA guidelines suggest amphotericin B for unstable patientsunstable patients
Echinocandin for Echinocandin for C. glabrata C. glabrata oror krusei krusei
Treat for 2 weeks after last + BCxTreat for 2 weeks after last + BCx
SummarySummary
Decision to attempt CVC salvage should be Decision to attempt CVC salvage should be made case-by-case, but many can be savedmade case-by-case, but many can be saved
Many (most?) Many (most?) S. aureus S. aureus and virtually all Candida and virtually all Candida infections mandate CVC removalinfections mandate CVC removal
Antibiotic lock therapy is promising, and Antibiotic lock therapy is promising, and probably still underutilizedprobably still underutilized
Revised guidelines in progress! Revised guidelines in progress!