1. Resistant Organisms and Nosocomial Infections: MRSA and CRBSI
Jim Pile, MD, FACP
Divisions of Hospital Medicine and Infectious Diseases
CWRU/MetroHealth Medical Center

2. Disclosures
Advisory Boards:
-- Baxter
-- Ortho-McNeil
-- Pfizer

3. What We'll Cover MRSA Catheter-related bloodstream infection (CRBSI)
- Epidemiology
- Clinical aspects
- Controversies surrounding vancomycin
- Alternative agents
Catheter-related bloodstream infection (CRBSI)
- Diagnosis
- Prevention
- Treatment

4. A 35 Year Old Man
Is admitted with a several day history of a "boil" on his right upper arm. The area has become increasingly tender, and "feels like it has pus in it." He noted chills and subjective fever last night, and states he has had 2 similar episodes in the past 6 months. On exam, he has a T of 38.0º C, with BP of 138/84, HR 94. A 6 cm abscess is present on the lateral aspect of his R upper arm, with modest surrounding cellulitis. Exam is o/w normal.

5. A 35 Year Old Man
He reports throat swelling with vancomycin, and hives with sulfa drugs
Does he need antibiotic therapy, or will drainage suffice?
If "yes," which antibiotic will you choose?
Should he be cultured for MRSA colonization, and if + should decolonization be attempted?

7. MRSA Arose from single clone Carry mecA gene, located on SCC
5 types of SCCmec, which code for antibiotic resistance
Spread of SCCmec from MRSA to MSSA isolates well-documented
> 50% of Staph aureus isolates from U.S. hospitals
mecA common to all MRSA, codes for PBP-2a, conferring B-lactam R. SCC is a mobile genetic element. SCCmec-I-III are MDR, HA; while mec-IV and V are not MDR, CA.

8. The Emergence of CA-MRSA
CA-MRSA first reported from remote communities in Western Australia as well as indigenous of northern CA in early 1990s. Then appeared in pediatric pts in US in late 1990s (outbreak of severe dz in Native American children in MN/ND--4 fatalities), and fairly quickly into athletes, prisons, MSM, day care, military, Indian reservations.

9. Community-Associated MRSA (CA-MRSA)
Most U.S. isolates are SCCmec-IV
Majority stem from single clone: USA300 strain
Almost all have Panton-Valentine leukocidin (PVL)
- Purulent SSTIs
- Necrotizing fasciitis
- Necrotizing pneumonia
PVL is almost certainly a virulence factor, encodes a toxin that attacks cell membranes and leukocytes--but exact contribution of PVL, vs other novel genes in CA--MRSA, still somewhat unclear. Predominant strains of CA-MRSA in Asia and Europe are distinct from that in US.

10. Extent of the Problem: 8/04
422 patients with acute, purulent SSTIs
MRSA in 59% (range, 15-74%)
97% of MRSA USA300
100/175 antibiotic courses were 'wrong'
Moran, NEJM 2006;355:666
Antibiotic Sensitivities:
TMP/SMX: 100%
Rifampin: 100%
Clindamycin: 95%
Tetracycline: 92%
Quinolones: 60%
Erythomycin: 6%
U of Chicago/ITL debate--end of EDs around US, making up EMERGEncy ID Net. % of SA that were MRSA varied from 15-74% between centers: low in NYC, high in KC. ¼ of pts had risk factors for HA-MRSA, BUT 98% of these had CA-MRSA. In contrast, only 3% of SA isolates submitted to MN labs in 2000 were MRSA. 13% of MSSA isolates were clinda R.

12. Moran et al, NEJM 2006;355:666

13. Changing Epidemiology of Nosocomial MRSA Infection
Harbor-UCLA study found CA-MRSA made up increasing proportion of nosocomial MRSA infxs
Stroger/Cook County: % of nosocomial MRSA BSI due to CA-MRSA rose from 24% in to 49% in
Maree, EID 2007;13:236
Popovich, CID 2008;46:787
UCLA-Harbor: all cultures (blood, wound, sputum) obtained > 72 hrs after admission. Incidence rose from 17% in 1999 to 56% in Cook County: similar clinical outcomes in both groups. Overall incidence of MRSA (all) unchanged between 2 periods. Authors cite 2006 ICAAC abstract of their research, modeling replacement of HA-MRSA by CA-MRSA; with emphasis on higher growth rate and superior fitness. Grady study in 2006 (CID) with similar findings--20% of nosocomial MRSA BSIs were CA-MRSA.

14. Multi-Drug Resistant CA-MRSA: More Bad News
Retrospective study of CA-MRSA from SF hospitals, SF/Boston clinics
MDR CA-MRSA highly associated with MSM
Raises ? of epidemic of difficult-to-treat CA-MRSA
Diep, Ann Intern Med 2008;148:249
MDR CA-MRSA recently reported from SF/Boston (and now NYC, LA). pUSA03 plasmid responsible for R to TCNs, clinda, mupirocin. Retrospective study of + MRSA cxs from SF hospitals in found that MDR CA-MRSA clone highly linked to residence in high-incidence male same-sex couple zip codes, with highest incidence in Castro. Study also looked at MDR USA300 infxs in SFGH HIV clinic, Fenway Community Health Clinic in Boston. 30% of MDR MRSA infxs in former and 47% in latter on perineum/buttocks. At Fenway, MDR USA300 exclusively found in MSM. Post hoc analysis of CA-MRSA isolates from Moran NEJM study (collected in 2004) found only 2 were MDR USA of these from known MSM. Authors of study suggest that presumed fitness cost of MDR seemingly now overcome by USA300. Concerns: a) spread throughout MSM population b) spread to general population c) incorporation of further transposons into pUSA03 plasmid conferring R to vanco, TMP/SMX, etc. Grounds for caution in treating MSM pts with clinda or TCN?

15. MRSA vs MSSA Bacteremia: Does it Matter?
2003 meta-analysis suggested worse outcome for MRSA
Pooled hazard ratio of 1.93 for MRSA
Appeared to hold up even when co-morbidities and severity of underlying illness controlled for
Cosgrove, CID 2003;36:53
Variability of studies: majority have not shown clear difference, although some studies show worse outcome for MRSA. NO study has shown worse outcome for MSSA. Meta-analysis pooled 4000 pts, with above forest plot summary. Reasons for worse outcome: glycopeptide inferiority? Delayed admin of effective abts? Generally felt that MRSA not intrinsically more virulent than MSSA.

16. CA-MRSA vs CA-MSSA: Not So Much?
Single-center Taiwanese study examined outcome in pts admitted with CA-MRSA vs CA-MSSA bacteremia
More SSTI and pneumonia in MRSA group, more endovascular infection in MSSA
30-day survival: 90% (MRSA) vs 87% (MSSA); p=0.62
Wang, CID 2008;46:799
30 pts in CA-MRSA, 185 CA-MSSA—all pts met criteria for community-acquired SAB. Most CA-MRSA were SCCmec-V--ie, NOT USA300. May help to address concerns by some that CA-MRSA may prove to be more virulent than traditonal HA-MRSA strains (because of PVL, etc)—but 10% vs 30% rate of endovascular infx in 2 groups.

17. Does Our Patient Require Antibiotic Therapy?
Several studies have suggested that CA-MRSA skin infections may not require abts after adequate drainage (all small/flawed)
492 patients, 531 episodes of CA-MRSA SSTIs
41% received inactive antibiotics
8.5% treatment failure: 5% with active abt, 13% with inactive (OR 2.80, p=.001)
Ruhe, CID 2007;44:777
Prior study suggested that if abscess </= 5 cm and properly drained, abts not necessary--in this study, abscess size not predictive of failure. This study did NOT classify as failure if pt worsened on inactive Tx, then improved after switch to active abt alone--thus, may have UNDERESTIMATED benefit of appropriate abt therapy. 2 tert care centers in Little Rock.

18. MRSA Colonization Colonization typically precedes infection
Is eradication of colonization possible?
Does eradication of colonized state prevent infection?
Mupirocin + chlorhexidine + rifampin + doxycycline vs no treatment
-74% vs 32% MRSA-free at 3 months
-54% MRSA-free at 8 months
Simor, CID 2007;44:178
Various studies have yielded different conclusions. Some studies of intranasal mupirocin suggest benefit, at least in short term, others have not Cochrane syst review found "insuffic evidence exists to support use of topical or systemic antimicrob therapy for eradicating MRSA". Important to keep concerns of resistance, AEs in mind as well--25% of pts in Simor study had GI side effects, 5% stopped therapy for same. Study used tid mupirocin, bid chlorhex, doxy 100 bid and rif 300 bid pts, randomized 3:1 to Tx/no Tx. 20% baseline mupirocin R, which predicted failure to be MRSA-free at 3 months.

19. Should Decolonization be Attempted in Our Patient?
Criteria for attempting decolonization not well defined
Importance of CA-MRSA at extranasal sites
If attempted:
-Consider multi-modality therapy
-Be cognizant of AEs
-Remember decay of results
Some data suggest that CA-MRSA less likely to colonize nares, more likely to colonize other sites c/w other MRSA. Detection of MRSA should probably not be limited to nares, but also rectum/perianal area, wounds, groin, ? Axillae.

20. Whither Vancomycin (Wither Vancomycin)?

21. Vancomycin: A Short History
Isolated in early 1950s, from S. orientalis
Early preparations markedly impure
Little used, due to
A. advent of antistaph B- lactams
B. oto, nephrotoxicity
Dosing/monitoring issues
Missionary in Borneo sent to his friend, organic chemist EC Kornfeld at Eli Lilly. "Mississippi Mud" due to brown color. Name derived from "vanquish" Toxicity issues clearly appear to have been largely/completely due to impurity issues--vanco probably not ototoxic, and has low incidence of nephrotoxicity. Typical dose schedule of 1 g q12h appears to have been selected arbitrarily. NO good evidence linking levels to outcomes--many moved away from routine levels.

22. Vancomycin Use, 1975-1996 (Levine, CID 2006;42:S5)
1981 RID supplement: “Vancomycin—a potentially useful antibiotic”(!) Twin issues drove rapid increase in use: emergence of MRSA in US HCF, and recognition of CDAD as a new/mounting problem. Graph shows escalating use of vanco in US and Western Europe (mainly former).

23. Vancomycin: A Suboptimal Agent for Staph aureus
Recent case-control study of MSSA bacteremia: mortality 37% with vanco, 11% with B-lactams (p<0.01)
54 cases of MSSA bacteremic pneumonia treated with vancomycin or cloxacillin: mortality 47% vs 0%
123 ESRD pts with MSSA bacteremia treated with vanco or cefazolin: 31% vs 13% failed treatment, OR 3.5
Kim, AAC 2008;52:192; Gonzalez CID 1999;29:1171; Stryjewski, CID 2007;44:190
Levine study: IVDU pts in Detroit, treated with either vanco or vanco + rifampin. Duration of bacteremia and fever sign longer than for historical MSSA controls treated with B-lactams. Gonzalez study from Spain. Recent study from S. Korea (Kim et al, AAC 1/08) showed significantly higher mortality for pts with MSSA bacteremia treated with vanco c/w those treated with B-lactams.

24. Time-Kill Curves for MSSA (from Stevens, CID 2006;42:S51)
From 1990 study of IVDU in SF, showing suboptimal response to vancomycin. Other studies support idea that killing of MSSA by vancomycin is slower than that of B-lactams.

25. Mounting Concerns Over Vancomycin Effectiveness
Growing sense that efficacy against MRSA may be lessening
Emergence of VISA, VRSA
--VISA: MIC 4-8 mcg/ml; VRSA: ≥ 16 mcg/ml
Phenomenon of heteroresistance (hVISA) a much bigger problem at present
--Heterogeneous population of MRSA, with a sub-population unresponsive to vancomycin despite reported sensitivity

26. MIC Uncertainties
Based on mounting data, MRSA susceptibility breakpoint for vanco changed from ≤ 4 mcg/ml to ≤ 2 mcg/ml in 2006
Many labs have difficulty with MRSA MICs
≤ 2 mcg/ml, however, still does not confirm true susceptibility
15% of strains with very low MIC by reliable testing still vanco tolerant!
Many labs still routinely using automated systems and/or disk diffusion to determine MRSA vancomycin MICs, which have been shown to be unreliable, and won't detect many elevated MICs. Broth microdilution and E-testing better, but more laborious. MIC ≤ 2 still no guarantee, as worse outcome appears to start with any MIC over 0.5 (see next slide). 15% of strains with very low MIC tolerant when tested for MBC.

27. MRSA MIC vs Vancomycin Failure Rate (Stevens, CID 2006;42:S51)
Adapted from Moise-Broder, CID 2004;38: Note that based on multiple studies, MIC creep nationally and internationally appears to be a real phenomenon.

28. agr Polymorphism: Still More Trouble?
agr gene cluster regulates a variety of key virulence and metabolic pathways
Down-regulated function appears to confer tolerance to vancomycin; MIC may still be very low
Have low vanco levels in past driven emergence?
Sakoulas, CID 2006;42:S40
4 agr types; I and II seem associated with vancomycin tolerance. Moise-Broder looked at 87 pts with MRSA infxs, and found that 31 of 36 with agr-II polymorphism failed to respond to vanco, whereas only 14 of 51 without this failed to respond. Sakoulas et al suggest that poor lung penetration with subinhibitory concentrations, weekly HD vanco dosing, aiming for low troughs based on concerns for oto/nephrotoxicity etc. may have led to tolerance issues.

29. MRSA Pneumonia Issues
Evidence suggests that a vancomycin trough of 4-5X the MIC may be optimal for serious MRSA infections
Penetration of vancomycin into lung only 20-30% of that achieved in serum
It may be difficult to achieve adequate concentrations of vancomycin in the lung, particularly if the MIC of the organism is relatively higher
Note that approximate 50% protein binding of drug raises necessary trough still higher, at least in theory.

30. Will High-dose Vancomycin Overcome These Concerns?
95 pts with nosocomial MRSA infections (low vs high MIC: ie, ≤ 1 mcg/ml or > 1 mcg/ml)
Study targeted aggressive vancomycin trough levels
Even with achievement of high trough levels, outcome worse in high MIC group: 62% vs 85% response (p=.02)
Uncertain whether benefit associated with high troughs Hidayat, Arch Intern Med 2006;166:2138
Note recommendation of 2005 ATS/IDSA guidelines for vanco trough of mcg/ml for HAP. Study showed better initial response in high-MIC group if target trough reached, but their final response rate was not better c/w low trough group. (Target trough: 4x MIC, doubled to account for 50% protein binding.) Excess nephrotoxicity seen in high trough group, but confounded by MUCH higher use of AG/AMB in this arm.

31. "There is an antibiotic called mud
That's proving to be quite a dud.
Its provenance is jungle
Its use is a bungle
It just won't get rid of your crud"
-Stan Deresinski, MD
CID 2007;44:1543

32. Trimethoprim/Sulfa and MRSA
1992 study of 101 IVDU pts with serious Staph aureus infxs: 86% cured with TMP/SMX, 98% (!) with vancomycin
No failures in either group with MRSA (47%). Authors concluded vanco superior, but TMP/SMX a valuable alternative
Markowitz, Ann Int Med 1992; ; Proctor, CID 2008;46:584
Sulfa and TMP sequentially block folate synthesis, leading to suppression of thymidine synthesis. Thymidine MAY be able to overcome effect of TMP/SMX, and may be produced by pus/high inoculums of staph aureus. Sulfa alone static for SA, but TMP/SMX cidal (albeit slowly). AIM study: included both MSSA/MRSA; 65% of pts bacteremic (IE, sepsis, OM, septic jts, cSSTI). P= % of MRSA organisms were clonal, MBC low for all tested strains (ie, may have helped explain phenomenal vanco response). Of note: ALL MRSA pts successfully treated in both arms. Recent review by Proctor calls into question efficacy of TMP/SMX for MRSA, saying use for CA-MRSA 'should not be endorsed without further research'--but overall LIMITED data seems to suggest somewhat o/w. At case report level, IE and meningitis have been cured with TMP/SMX.

33. Tetracycline and Clindamycin Treatment of MRSA
Retrospective study of 24 pts with MRSA infxs treated with long-acting tetracyclines: 83% cured
Review of world literature: 85% of 85 pts treated with TCNs responded well
Ruhe, CID 2005;40:1429
Clindamycin: most MRSA strains remain sensitive
Some data suggest efficacy in children with serious MRSA infx
Very limited data in adults
Ruhe TCN study: at U of AR. Majority had cSSTI, one quarter had invasive infx. Tx well tolerated in virtually all. Doxy and mino well absorbed, good tissue penetration. Most of cases in world lit review had cSSTIs, both MSSA and MRSA. 85% of North American MRSA strains S to TCNs. Key that E-testing be performed in MRSA isolates showing R to erythro, S to clinda to identify inducible R.

34. Daptomycin Cyclic lipopeptide, rapidly bactericidal against S. aureus
2006 study of daptomycin vs standard therapy for MRSA, MSSA bacteremia
-Daptomycin "not inferior" to standard treatment
2004 cSSTI trial, dapto vs standard tx:
-83% vs 84% cure
Daptomycin NOT appropriate for pneumonia
Fowler, NEJM 2006;355:653 Arbeit, CID 2004;38:1673
NEJM study: randomized, open-label, dapto + either vanco or antistaph PCN for MRSA/MSSA bacteremia. Similar outcomes, but more failures in dapto group due to non-response, more in standard group due to AEs. Trend toward better outcome with standard Tx in MSSA group, but outcomes appear likely equal in MRSA group (results a bit opaque since failure reasons not listed for all subgroups). Note CK elevation in 1/4 of dapto (though usually not show-stopper), emergence of dapto R in 7 pts during Tx. In cSSTI trial, compared to vanco or antistaph PCN, at discretion of investigator (ie, vanco if felt high risk for MRSA). Daptomycin CAN'T be used for pneumonia: poor levels in lung, and inactivated by surfactant (unique problem). Decreased S to vanco may predict same to dapto. Some now routinely use 8 mg/kg/day for BSI and other deep infxs (? Effect on CK).

35. Linezolid vs Vancomycin in Nosocomial Pneumonia
RCT comparing linezolid + aztreonam to vanco + aztreonam for nosocomial pneumonia
--204 evaluable pts: clinical cure (66% linezolid, 68% vanco), mortality equivalent
Continuation study: 345 patients evaluable, clinical efficacy/mortality again equivalent (cure in 68% vs 65%; mortality 20% both arms)
Rubinstein, CID 2001;32:402; Wunderink, Clin Ther 2003:25:980
Linezolid is bacteriostatic, not cidal. SA causes approx 20% of ICU nosocomial pneumonia (NNIS data) and 600+ pts randomized to ITT in above studies, but many fell out for various reasons. Vanco dosing, importantly, was 1 g q12h. More than 50% of pts in first study on vent at outset of study. Investigators concluded 2 drugs equally effective and safe for nosocomial pneumonia Tx.

36. Wunderink, RG. Linezolid vs vancomycin: analysis of 2 double-blind studies of patients with MRSA nosocomial pneumonia. Chest 2003;124:1789
Retrospectively analyzed 2 prior studies, looking specifically at outcomes in Staph aureus pts, and those specifically with MRSA pts had SA, 160 of whom had MRSA (apparently of ALL 1019 enrolled in the 2 studies, not just those 'clinically evaluable'). Overall survival rates (for nos pneumonia): 81% linezolid, 78% vanco, p= Staph aureus: 78 vs 71%, p= MRSA: 80 vs 64%, p= SA cure rate: 52% vs 43%, p=0.18; MRSA 59% vs 36%, p= After logistic regression analysis, difference remained significant after adjustment. Penetration of linezolid into lung excellent, exceeds plasma conc. 2 flaws in study: post hoc analysis, and ? underdosing of vancomycin.

37. Other Existing Agents Quinupristin/Dalfopristin Tigecycline
Tigecycline: has compared well to vanco + aztreonam in cSSTIs. Not approved for BSIs, and some concern that serum concentrations may be suboptimal for BSIs. N/V issues (but ? Somewhat overblown?) Synercid: Limited data vs MRSA. Use limited by need to administer via central line, and high rates of myalgias/arthralgias complicate use. One trial of Q/D vs vanco in nosocomial pneumonia showed strong trend toward vanco superiority for MRSA. Has appeared effective in Tx of OM/septic arthritis/SSTIs, perhaps less so against BSIs.

38. In the Pipeline Dalbavancin Ceftobiprole Iclaprim Oritavancin
Telavancin
Dalba: semi-synthetic glycopeptide, 'lipoglycopeptide'. Very long half life (up to 250 hrs), once weekly dosing. Phase 2 studies look good, large phase 3 in cSSTI showed equivalence to linezolid (CID 2005). Thus far appears safe/well tolerated. Clear potential role for dose upon hospital d/c, outpt therapy avoiding PICC, etc.--but COST?? Ceftobiprole: "5th generation" cephalosporin with activity against MRSA (and VISA/VRSA), as well as fairly broad GNB coverage. Has compared well in 2 trials of cSSTI vs vanco + ceftaz, vanco alone. Other B-lactams active vs MRSA under development. Will this have more activity against MRSA than other drugs, similar to B-lactams and MSSA? Probably not active against ESBLs. Iclaprim: folate antagonist with bactericidal activity vs MRSA. Oritavancin: long 1/2 life, dosing will be qday or qod. Televancin: daily dosing, has compared well to vanco in trials of cSSTI (as has oritavancin).

39. Summary
The epidemiology of MRSA continues to evolve, with CA-MRSA moving into the hospital
Most CA-MRSA strains remain sensitive to multiple antibiotics--for the moment
Vancomycin MAY still be the drug of choice for serious MRSA infections, but leaves much to be desired
Multiple alternatives exist, with more coming

40. CRBSI: Diagnosis, Prevention and Management
Robert Hickman (inventor of HC in mid-1970s) in John Broviac, a nephrology fellow at UW, developed first indwelling central catheter in 1968, made out of Silastic. Hickman subsequently developed multi-lumen catheter in As of last year (age 80) he was still inserting catheters at the Fred Hutchinson Cancer Center. Aubaniac credited with first CVC (SCV) in 1952, with progressive improvements in short-term CV access : Arrow introduces first CVC kit (bedside), and in 1982 introduces first multi-lumen non-tunnelled CVC.

41. Clockwise: Mediport, Groshong, non-tunneled CVC, PICC
Clockwise: Mediport, Groshong, non-tunneled CVC, PICC. Tunneled caths inserted via 2 incisions, anchored with subq cuff which provides at least some resistance to external colonization of CVC.

42. A 54 Year Old Woman with an Entero-cutaneous Fistula . . . .
After colo-rectal surgery and receiving TPN via a Hickman catheter presents with 2 days of fever to 102° F and no other symptoms. Her T on presentation is 38.8° C, her BP/HR are essentially normal, and her catheter exit site and tunnel are not inflamed. The remainder of her physical exam is unrevealing.

43. A 54 y.o. with an ECF
Should the catheter be removed on arrival?
If not, how will you decide whether it is the culprit?
If you decide the catheter is infected, will the offending pathogen influence your decision to remove it?
If the catheter is retained, how will you treat the infection?

44. Scope of the Problem
> 5 million catheter-related infxs in US annually
? 200K infections
80K CRBSI in U.S. ICUs, estimated 28,000 deaths
CRBSI cost estimates/episode $3K-$50K
? > $2 billion per year
Raad, Lancet ID 2007;7:645; Pronovost, NEJM 2006;355:2725
Note that most of infxs are CRBSI, though some are exit/tunnel infxs in absence of BSI. Attributable mortality in ICU pts reported between 12-25%, though AM only 3% in one meta-anal of all comers. In general, AM associated with SA clearly higher than for other pathogens, and that associated with CNS less.

45. Pathogenesis of CRBSI Non-tunneled CVCs: 1. Extraluminal colonization
2. Colonization of hub and catheter lumen
3. Hematogenous seeding of catheter
Tunneled CVCS:
-Hub contamination/intraluminal colonization
Importance of role of biofilm in persistence of intraluminal colonization/infx

46. Diagnosis of CRBSI Frequently not straightforward
Exit site inflammation: relatively specific, but very insensitive
Catheters frequently not the culprit in pts with unexplained fever (and may not be source of bacteremia)
How can non-infected CVCs be distinguished?
1999 study found that NPV of negative BCx through line 99% for CVC infection.

47. Quantitative Blood Cultures
Blood Cxs drawn simultaneously from CVC and peripherally
≥ 5-fold higher colony count from CVC considered diagnostic of CRBSI
Non-tunneled CVCs: sensitivity 82%, specificity 89%
Tunneled (long-term) CVCs: S/S 83%/97%
Both expensive and laborious
Safdar, Ann Intern Med 2005;142:451
Many micro labs unable to perform.

48. Differential Time to Positivity
Blood cultures obtained simultaneously from CVC and peripherally
CVC culture reported + at least 2 hours before peripheral considered diagnostic for CRBSI
Sens/specif 89%/87% for short-term catheters; 90%/72% for tunneled catheters
Simple and widely available
More cost-effective than quantitative techniques
Mermel CID 2001;32:1249; Safdar Ann Intern Med 2005;142:451
Importance of labeling key!! Other, probably not ready for prime time dx techniques: quant cxs from CVC only, endoluminal brush (PE, arrhythmia, biofilm disruption).

49. CRBSI Prevention: Antiseptic Practice
Hand hygiene
HCW education
Regular surveillance of catheter site
Maximum sterile barriers
2% chlorhexidine skin prep
Removal of unnecessary catheters
Don't routinely replace non-tunneled CVCs
Use subclavian vein when possible
MMWR 2002;51/RR-10
Education: indications for CVCs, proper procedures for insertion/care. Surveillance of site: "visually or by palpation". Max sterile barriers: gown/gloves/hair cover/large drape. PA catheter study showed lower rate of BSI; CVC study showed strong trend toward less BSI (p=0.06). A-line study did not support benefit.

50. MHA Keystone ICU Project
103 ICUs in Michigan, 375K CVC days
Comprehensive unit-based education, daily goals sheet, and VAP intervention as well
Included 5 key measures: hand hygiene, full sterile barriers, chlorhexidine use, avoidance of femoral site, removing unnecessary CVCs
Central line carts created, nurses empowered, checklists used to increase compliance
Pronovost NEJM 2006;355:2725
Study involved 85% of ICUs in MI. Several smaller studies had suggested that implementation of CVC 'bundles' effective in lowering risk of CRBSI. Study designed to look at quarterly rates of CRBSI.

51. Keystone ICU Study
Significant reduction in rate of CRBSI in quarter of implementation
Results sustained over duration of study
CRBSI fell from mean of 7.7 to 1.4 infections per catheter day
Improvement not only sustained but increased over time. Ironically, Office of Human Research Protection/"HIPAA violation" flap has further highlighted project.

52. "The structure of the intervention involved daily commitment to a culture of safety We can no longer accept the variations in safety culture, behavior, or systems of practice that have plagued medical care for decades. Imagine the effect if all 6000 acute care hospitals in the US were to show a similar commitment and discipline."
-Richard Wenzel, MD

53. Antimicrobial Catheters
Silver-impregnated catheters
Antiseptic catheters
Antibiotic-coated catheter
CDC: "consider" use of impregnated catheter when expected to be in place > 5 days
Silver: silver, platinum and carbon bonded to catheter. 2 studies examining BSI rate have failed to show benefit, though rates of colonization are lower. Antiseptic caths: 16 trials of 1st gen (externally coated) caths (sulfadiazine silver and chlorhexidine), most show decreased colonization rates but only 2 show less BSI. 3 trials of 2nd gen (externally/internally coated) show sign decrease in colonization, but no sign change in BSI (underpowered?). Abt-coated caths: 1 available, minocycline/rifampin ext/internal coating. 5 studies show reduced rate of BSI. Concerns re: emergence of resistance, not yet seen. Sanjay's cost effectiveness analysis in Am J Inf Control (2003) concluded rif/mino cath cost effective when used 1 week or longer. Prophylactic abt lock therapy has been studied with vanco, EDTA/minocycline and 25-40% ETOH--role unclear, ? for pt with repeated CVC infxs (per 2001 CDC prevent guidelines).

54. CRBSI Management: Key Questions
1. Is the catheter truly the culprit?
2. Does the catheter need to be removed?
3. What type of antibiotic therapy?
4. How long should the infection be treated?
As already noted, CVC may not be the culprit. Negative predictive value of neg BCx drawn through CVC very high (99% in 1999 DesJardins AIM study) study found that of CVC removed due to suspected infx, 71% were sterile.

55. Deciding When to Remove the Catheter
Tunneled vs non-tunneled CVC
Hemodynamic instability
Identity of pathogen
Complicated infection
Tunnel/port pocket infections
IDSA guidelines: "CVCs in pts with fever and mild-mod dz should not be routinely removed" BUT "in most cases of non-tunneled CRBSI, the cath should be removed."--retention of short-term cath can be considered in stable pt with CNS. Exit site infx should prompt removal of non-tunneled CVC. Complicated infx: endocarditis, septic pulm emboli, susp of septic thrombus, OM, heart valve abnls, etc.

56. Antibiotic Lock Therapy
Failure appears to frequently relate to inability to kill organisms in luminal biofilm
Antibiotic concentration may need to be X greater to kill bacteria in biofilm
ALT: 2-5 cc of antibiotic solution instilled into lumen(s) and "locked"
83% cure rate vs 67% with conventional therapy only
Mermel CID 2001;32:1249
Antibiotic may be mixed in either heparin or saline. Figures reported above from informal systematic review. Multiple additional studies support use of ALT (including HD catheters).

57. Coagulase Negative Staph
Leading cause of CRBSI in most series
Up to 80% of catheters salvageable
If catheter retained: 7 days systemic therapy, days lock therapy (ALT)
Catheter removed: 5-7 days systemic therapy
Weekly dalbavancin therapy promising
Mermel CID 2001;32:1249; Raad CID 2005;40:374
Potential difficulty in sorting out true CRBSI vs spurious. Unanswered questions: is vanco most efficacious ALT, or would alternative (minocycline/EDTA, ethanol) be more efficacious, as suggested by prelim data? Is any therapy needed if catheter removed in uncomplicated setting? Dalbavancin study randomized 75 pts (with CNS and SA) to IV vanco or dalba, 1000 mg followed by 500 mg 1 week later--better outcome in dalba arm in ITT analysis, although numbers not that large (mostly non-tunneled caths, CVCs removed if staph aureus, response to vanco lower than expected--?? if dalba really superior)

58. Staph aureus Strong association with metastatic infection
23% of S. aureus CRBSI had endocarditis in 1 study
Faster sx resolution/less relapse with CVC removal
Uncomplicated infxs with catheter retention: 14 days systemic + abt lock therapy
Fowler JACC 1997;30:1072; Mermel CID 2001;32:1249
1997 Fowler study showed 16/69 (23%) pts with CRBSI and SA had vegetations on TEE--very low sens of TTE in this study. Authors suggested all of these pts should have TEE, with neg study suggesting 2 weeks Tx sufficient. Very clear that systemic + ALT effective in reasonable % of cases, but data weak and inconclusive. Careful consideration needed when deciding whether to retain catheter. Persistent fever/bacteremia or metastatic infx mandates removal. Retention indicated in pts with severe thrombo, no other remaining access, etc--o/w less clear. Choices of abts: MSSA vs MRSA. 3 studies support quicker resolution/less relapse when CVC pulled.

59. Gram Negative Bacilli
Recent study reported cure in 13/15 HD catheter infxs (87%) with systemic + lock tx
"Tough" pathogens (S. maltophilia, B. cepacia, Acinetobacter, non-aeruginosa Pseudomonas) appear less likely to respond
Catheter removed: 7-14 days systemic abts
Catheter retained: 14 days systemic + ALT tx
Poole, Nephrol Dial Transplant 2004;19:1237; Raad Lancet ID 2007;7:645;
Mermel CID 2001;32:1249
Data re: GNB and CRBSI rather weak. If CVC removed, only 1% risk of relapse. 2 failures appeared to be d/t resistant Pseudomonas spp. Pull CVC for 'tough' bugs. Surveillance important in all cases where CVC retention attempted.

60. Candida spp
Multiple prospective studies support worse outcome with attempted CVC salvage
70% failure rate even with systemic + lock tx
IDSA guidelines suggest amphotericin B for unstable patients
Echinocandin for C. glabrata or krusei
Treat for 2 weeks after last + BCx
1998 study found retention of CVC in pts with nosocomial candidemia to be IRF for increased mortality. One study of 26 pts treated without removing CVC--4 pts developed endophthal, 3 lost sight. Ophtho exam for all candidemic pts. Most would currently use candin in unstable pt in this setting. Note 2007 Reboli study of anidulafungin vs flucon for candidemia, suggesting greater efficacy for flucon.

61. Summary
Decision to attempt CVC salvage should be made case-by-case, but many can be saved
Many (most?) S. aureus and virtually all Candida infections mandate CVC removal
Antibiotic lock therapy is promising, and probably still underutilized
Revised guidelines in progress!