Vancomycin and Vre

8/14/2019 Vancomycin and Vre

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Vancomycin & VancomycinResistant Enterococci

Abdullah M. Kharbosh, B.Sc., Pharm


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Objectives

Understand Vancomycin history, MOA, kinetics and spectrum

Aware of Vancomycin ADRs, their aggravating factors

Able to do Vancomycin dosing and dosing adjustment

Define VRE & understand its characteristics as an important MDR

nosocomial pathogen Differentiate between colonized and infected patient

Understand the treatment approach for VRE

Discuss the antibiotic recently introduced to the market

Identify practices that contribute to the development of VRE


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Class

Glycopeptide


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MOA


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Kinetics

Absorption:

- PO: Nil (Not for systemic infections)

- IV: 100%

- IM: Never

Distribution (2 compartment model)

o Widely distributed in body tissue and fluids

o Except CSF Half-life: 6-8 hrs, ESRD: 8-10 days

Elimination: Renal

Metabolism: Nil


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Spectrum

Gram-positive bacteria: Streptococci

Staphylococci

Enterococcus fecalis

Clostridium difficile


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Adverse Effects

Red-man syndrome

Nephrotoxicity

Ototoxicity

Other Phlebitis

Thrombocytopenia

Neutropenia

Eosinophilia Drug fever

Allergic reactions


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Red-Man Syndrome

What?

When?

Why? How To Manage?


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Nephrotoxicity

Mississippi Mud


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Nephrotoxicity risk factors

Length of therapy

Receiving other Nephrotoxic drugs e.g.

Amphotericin B

Aminoglycosides (trough, length of therapy)

Cyclosporine Vancomycin Trough > 15 mcg/ml, Peak >40mcg/ml

Having preexisting renal impairment

Liver disease

Neutropenia Peritonitis

Male six

Older age

Pharmacotherapy. 1990;10(6):378-82.


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Incidence < 2%, damage to 8th cranial nerve

Deafness, vertigo, dizziness, tinnitus

May be reversible or permanent

Reported with peak > 80 mcg/ml or rapid infusion

Commonly associated with vancomycin given witherythromycin or aminoglycosides

Ototoxicity


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Renal impairment

Receiving high IV doses for prolonged periods

Having preexisting hearing problems

Receiving other ototoxic drugs e.g.

Aminoglycosides

Cisplatin

Erythromycin Furosemide

Patients at risk


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Drug interactions

Non-depolarizing muscle relaxants

Succinylcholine, atracurium, vecuronium, pancuronium, tubocurarine

case reports of enhanced neuromuscular blockade

Monitor closely with co-administration

Cholestyramine

Binds to PO vancomycin

Do not co-administer

Consider PO metronidazole with cholestyramine co-administration

Aminoglycoside Higher incidence of nephrotoxicity associated with vancomycin and

aminoglycoside co-administration


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Vancomycin kills bacteria slower than B-lactams

Mean duration of Bacteremia

Vancomycin

MRSA Endocaritis 7 days

Nafcillin

MSSA Endocaritis 3 days

Higher mortality with Vancomycin treated patients vs. B-lactams

How Good an Antibiotic is Vancomycin?

- Conzalez: CID 29:1171,1999

- Levine, D: Ann. Intern. Med. 115:574,1999


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Dosing For appropriate dosing consider:

Infection site

Patient weight

Renal function

Concomitant high-flux hemodialysis


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CrCl (ml/min) Interval

>80 Q 12hr

60-79 Q 18hr

40-59 Q 24hr

20-39 Q 36hr

11-20 Q 48hr

< 10 *

Recommended Dosage: 15 mg/kg Q12H (based on actual body weight)Calculate creatinine clearance

Determine interval based on creatinine clearance

Adapted from Matzke, GR, et al. Antimicrob Agents Chemother 1984; 25:433.

* Give an initial single dose & adjust dose& interval based upon serum Conc.

Dosing


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TroughDurationDoseCondition

NA7-10 days125-250mg PO Q6HPMC

15-204-6 Weeks15 mg/kg Q12HOsteomyelitis

15-2014-21 days15 mg/kg Q12HHAP/VAP10-1510-14 days15 mg/kg Q12HBacteremia

15-104-6 Weeks15 mg/kg Q12HEndocarditis

15-2010-14 days15mg/kg Q8-12HMeningitis

- Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcareassociated pneumonia.; Am J Respir Crit Care Med; 2005; Vol. 171; pp. 388-416.- IDSA: Guidelines for Skin and Soft-Tissue Infections CID 2005:41 (15 November).- Practice guidelines for the management of bacterial meningitis.; Clin Infect Dis; 2004; Vol. 39; pp. 1267-84.

- The AHA 2005/IDSA Recommendations. Circulation. 2005;111:3167-3184.- Gerald L. Mandell, principles & practice of infectious diseases 6th ed.

Dosing


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Dosing (Pediatric)

Usual recommended dose: 40mg/kg/d divided Q6

Meningitis/Febrile Neutropenia: 60mg/kg/d divided Q6


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Dosing (Neonates)

Postmenstrual age

(Wk)

Postnatal age

(Day)

Dose interval

(Hrs)

< 30 < 15 18

15 or more 12

30-36 < 15 12

15 or more 837-44 < 8 12

8 8

> 44 All ages 6

Neofax 2007

Usual Recommended Dose: 15mg/kg/dose


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UsesAntibiotic-associated PMC caused by C. difficile

Enterocolitis caused by S. aureus (including MRSA)

Skin, soft tissue infections

Bone and joint infections

Pneumonia

Endocarditis


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Pseudomembranous Colitis/Enterocolitis

C. difficile PMC: 125mg PO q6h (higher doses 250-500mgPO Q6 may be given with ileus or severe disease) x 7-10 d

Staphylococcal EC: 500-2000 mg PO per day in 3-4 divideddoses x 7-10 d

PO preparation is not absorbed (ineffective for any infectionsother than C. difficile PMC & S. aureus EC)

IV formulation is not effective for treatment of staphylococcalEC & PMC caused by C. difficile

IV Vancomycin can be given orally for C. difficile PMC todecrease cost ($ 4 vs. $128 per day)


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Skin, soft tissue infections Vancomycin is the drug of choice for treatment of severe

skin and soft tissue infections due to MRSA

With less severe infection, many CA-MRSA can be treatedwith clindamycin, septrin or doxycycline

For small abscesses and less serious CA-MRSA skin or softtissue infections, drainage or local therapy alone may beeffective

In severely ill patients vancomycin or Linezolid should be

added until MRSA is ruled out Linezolid or daptomycin are reasonable alternatives

Tigecycline can also be used


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Osteomyelitis

S. aureus is the most common cause of osteomyelitis

For empiric treatment of osteomyelitis, IV administration of anantistaphylococcal penicillin such as oxacillin or a first-generation cephalosporin such as cefazolin would beappropriate

Some consultants would use vancomycin until cultureresults are available

If MRSA or CNS is the pathogen: Vancomycin or Linezolid(alternative) should be used


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Pneumonia (HAP/VAP)

Employed to cover the possibility of MRSA

Clinical failure rates 40%

Trough levels to keep level > 15 mcg/mL

Combine with Rifampin or Aminoglycosides

Alternative: Linezolid

May be preferred

On the basis of a subset analysis of two prospectiverandomized trials

Achieves excellent penetration into lung tissues and fluids

Preferred in renal insufficiency or receiving othernephrotoxic agents

But more data are needed


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Vancomycin is generally the DOC for bacteremia,endocarditis, & other serious infections caused by MRSA

Enterococcal endocarditis (HL PNC Resistance/PenAllergy)

S.pneumonia resistant to Pen/Ceph

Addition of Gentamicin 1mg/kg IM/IV Q8H to overcome

Slow response ,High failure rate (bactericidal effect,

reduce bacteremia duration)

Endocarditis


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Meningitis

The most commonly responsible organisms forcommunity-acquired bacterial meningitis in children &adults are S. pneumoniae (pneumococcus) & N.meningitidis ( 80% of all cases)

Vancomycin in usual doses may not reach effective levelsin cerebrospinal fluid and clinical response should becarefully monitored


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Should be considered Moderate to severe renal impairment Rapidly changing renal function Severe, life-threatening Gram-positive infections

Endocarditis Meningitis Sepsis

Vancomycin pharmacokinetics are likely to be

significantly altered Critically ill Septic Morbidly obese

Therapeutic Drug Monitoring

Moellering R. Clin Infect Dis 1994;18:544-5.


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What should be monitored?

Trough

Target: 10-15 mcg/ml (Specific:15-20mcg/ml)

Timing: 30 min pre next dose


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Indications for Trough Monitoring

IV treatment >4 days

Concomitant Nephrotoxic(S)

Morbid obesity

Rapidly changing/Unpredictable renal function


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Interpretation

If trough > desired: prolong dosing interval

If trough < desired: dose or dosing interval


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Vancomycin Resistant Enterococci(VRE)


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Definition Enterococci normally found in:

GIT

Female genitourinary tract

Relatively of low virulence, but may cause: UTI, intra-abdominal abscesses, bacteremia, endocarditis

Less common: Meningitis, osteoarticular infections

Vancomycin susceptible: MIC 4 mcg/ml

Vancomycin resistant (VRE): MIC > 32 mcg/ml

Gerald L. Mandell, principles & practice of infectious diseases 6th ed.


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Mechanism of Resistance


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Resistance Intrinsic Resistance (Its own, non-transferable)

B-Lactams

Aminoglycoside (LL)

Clindamycin

Erythromycin

Tetracyclines

Septrin


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Acquired Resistance Ampicillin, penicillin (HL)

Aminoglycosides (HL)

Quinolones Chloramphenicol

Glycopeptides

Quinupristin/dalfopristin

Linezolid Daptomycin

Resistance


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Clinical isolation of VRE

First case: France, 1986

First case in Saudi Arabia

In Riyadh Armed Force Hospital, 1993


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Epidemiology

From late 1980s mid 1990s the rate ofVRE isolates 34-fold

At 2000, of all enterococcal isolates are

resistant to Vancomycin

* Centers for Disease Control and Prevention (CDC) NNIS System. National Nosocomial Infection

Surveillance (NNIS) system report, 2000. American Journal of Infection Control, 28, 429-448.


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Nosocomial Pathogen

1st in surgical site infections

3rd in UTI & bloodstream infections

4th most common in ICU patients

Intra-abdominal infections

Rare but serious: Endocarditis, Meningitis

NNIS data from Jan, 1992 to Jul, 1998


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Why is important?

Increased prevalence

Increased morbidity, mortality

Transferring resistance

Limited treatment

Partial successful infection control efforts

Approaches to vancomycin-resistant enterococci Torres-Viera and Dembry. Current

Opinion in Infectious Diseases 2004, 17:541547


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E.faecalis vs. E.faecium

MortalityInfectionResistance

----85-90%3%E. faecalis

Higher10-15%51%E. faecium


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ICU vs. Non-ICU

Source: National Nosocomial Infections Surveillance (NNIS) System

0

5

10

15

20

25

30

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

%R

esistance

Non-Intensive Care Unit Patients

Intensive Care Unit Patients


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Risk Factors

Host Related Risk Factors

VRE colonization

Immunodeficiency

Transplant recipient Renal insufficiency (antibiotics,catheter,dialysis)

Severity of underlying illness

Perl, T. Delisle, S. (1998). The Emergence and control of vancomycin resistant Enterococci. Grand Rounds inInfectious Diseases, Scientific Exchange, Inc.


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Risk Factors

Hospital Related Risk Factors

ICU/Oncology/Dialysis Admission

Proximity to a patient with VRE

Length of hospitalization

Multiple unit stays

Enteral feedings /TPN (Catheters)


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Risk Factors Medication Related Risk Factors

Number, type, and duration of antibiotic therapy

Vancomycin (IV/PO)

3rd generation cephalosporin (Ceftazidime,ceftriaxone)

Anti-anaerobic antibiotics (such as clindamycin,imipenem, metronidazole)

Ciprofloxacin

Clin Infect Dis. 1997 Sep;25 Suppl 2:S206-10.


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Colonization Colonization usually acquired by susceptible hosts in an

environment with a high rate of patient colonization withVRE (e.g., intensive care units, oncology units)

Source of infection

At an increased risk for VRE infection (Relative risk of 3)

Clinical Infections

Colonized


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Infection VRE usually develops in colonized patients Infected-to-colonized ratio is dependent on the specific patient population

in hematology, organ transplant and severely ill patients

Approaches zero in healthier populations (immunocompetent)

Portals of VRE entry typically include:

The urinary tract

Intra-abdominal (e.g., GIT, biliary tree)

Pelvic sources

Wounds (surgical wounds, decubitus ulcers)

Intravascular catheters

(VRE Skin colonization Catheter

colonization Catheter related sepsis

Mayo Clin Proc. 2006;81(4):529-536


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Anything happen while I was on vacation?


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Management of Vancomycin

Resistant Enterococci


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Treatment

Optimal treatment?

ID consultation

Follow sensitivitiesTreat only those infected not colonized


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Non-Antimicrobial Treatment

Catheter or device removal

Abscesses drainage


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1st line (DOC): Linezolid (E.faecium, E.faecalis) 600 mg IV Q12 (watch PLT,WBC#), switch to PO when stable

Alternatives:

2nd line: Quinupristin/dalfopristin (E.faecium only)

7.5mg/kg IV Q8

2rd line: Daptomycin (E.faecium, E.faecalis)

Skin/soft tissue: 4mg/kg IV Q24

Bacteremia/Endocarditis: 6mg/kg IV Q24

Tigecycline

100mg IV loading dose, then 50mg IV Q12

Nitrofurantoin, Fosfomycin: UTI only

Approach To Therapy


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Teicoplanin The cross-resistance shown by many isolates to Teicoplanin

has limited its use as an alternative agent


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Class: Oxazolidinedione MOA: Binds P site of 50s ribosomal subunit,

preventing translation initiation

Linezolid


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Linezolid FDA approved- Adult (April 2000)/Children (Dec 2002) Gram (+)

Indications

VRE (E. faecium and E.faecalis)

Nosocomial pneumonia (S. aureus)

Community-acquired pneumonia (S. pneumoniae)

cSSSI (S. aureus)

IV or PO PKs the same, 600 mg bid, expensive

Currently, is the only PO FDA approved agent

DOC: Serious VRE infections (the most commonly used anti-VRE) Endocarditis ( 8 wks): disadvantage (static, lack of data)

Meningitis (4 wks)

No dose adjustment for renal or hepatic impairment

Resistance in VRE, MRSA has occurred


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Adverse drug reactions: GI intolerance (nausea, vomiting, diarrhea)

Myelosuppression: thrombocytopenia, neutropenia, leukopenia (>2wk)

Most common serious ADR

May limit its use in some patients Reversal of Cytopenias but not peripheral neuropathy by Vit.B6???

Neuropathy - optic/peripheral (> 28 days)

Lactic acidosis (usage duration independent)

Reversible, non-selective MAO inhibitor

MAO inhibitors- tyramine containing food, decongestants, SSRIs

Stop 14 days before initiating linezolid

Linezolid


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Attractive compare to Vancomycin in patients

With renal impairment

Poor or no IV access

Require outpatient therapy Unable to tolerate glycopeptides

Linezolid


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QuinupristinDalfopristin Streptogramin, static, inhibit protein synthesis FDA approved- 1999

Gram (+): VRE (not E.faecalis) bacteremia, MRSA (cSSSI, HAP)

Parenteral (via central line) / Extremely expensive

2nd line: Serious VRE infections

Useful in if Linezolid caused neutropenia/other hematological ADRs

Adverse drug reactions:

Infusion site pain, inflammation & thrombophlebitis

1/3 of patients develop arthralgia/myalgia

Drug interactions: CYP3A4 inhibitor e.g. Cyclosporine, Nifedipine levels


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Class: Cyclic lipopeptide, bactericidal MOA: In the presence of Ca2+, Binds membrane Rapid

depolarization Cell death

Daptomycin


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Daptomycin Cyclic lipopeptide, bactericidalActive vs. VRE (E.faecalis, E.faecium)

Parenteral, once daily

3rd line choice: Quite limited data Should not be used to treat pneumonia

Dose if Crcl < 30ml/min: 4 mg/kg once Q48H

Adverse drug reactions: Toxicity-dose dependent CK elevation, myopathy

Resistance may occur during treatment


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An organic phosphonate, broad-spectrum, bactericidal Approved for the treatment of uncomplicated UTIs

Dose: 3 gm sachet PO x 1 dose In 3 randomized trials, a single 3gm dose was compared with

nitrofurantoin 50mg Q6 X 7d, norfloxacin 400mg Q12 X 5 d,and cephalexin 500mg Q6 X 5 d (n:400 women) Eradication rates were similar to those with norfloxacin and

nitrofurantoin and superior to those with cephalexin*

Useful alternative to Linezolid & QD in uncomplicated UTIs Limit their use, thus development of further resistance

ADRs:The most common diarrhea, 10%

Interaction:Antacids (CaCO3)/ Food : Absorption

Fosfomycin

* Z de Jong et al, Urol Int, 46:344, 1991; E Van Pienbroek et al, Pharm World Sci, 15:257, 1993;G Elhanan et al, Antimicrob Agents Chemother, 38:2612, 1994


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A semi-synthetic Tetracycline, static, broad-spectrum Approved for:

Complicated SSSI (MRSA & Vancomycin-susceptibleE. faecalis)

Complicated intra-abdominal infections

In intra-abdominal infections/complicated SSSI (moreconvenient Q12 dosing compared to imipenem/cilastinand piperacillin/tazobactam

Off-label use: VRE Non-life threatening SSSI

Can be used, but because it has a very broad spectrumof activity (reserved for patients unable to take otherdrugs or with documented polymicrobial coinfection

ADRs:Nausea & vomiting may occur in up to 1/3 of patients

Tigecycline


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Due to its ability to achieve high urinary Con. has been shownto be effective in VRE UTI Dose

Monohydrate: 50-100 mg PO q6h or Macrocrystals 100mg PO bid Not appropriate for short course (3d) UTI therapy. Minim:7d

Cannot be employed for:

VRE outside the urinary tract

In patients with a Crcl


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Glycopeptides Vs. Available AlternativesRecently Introduced Into The Market

TigecyDaptoQ/DlinezTeicopVanco

NNNYNN*IV/PO bothavailable

???YYNOutpatient

NNYNNYNeed of TDM

Q12Q24Q24Q12Q24

Q12 to Q24Frequency ofADM

AbbreviationsY: Yes, N: NoTDM: Therapeutic Drug MonitoringADM: Administration

Note: *indication restricted to the management ofClostridium difficile-associated diarrhea.

Therapeutics and Clinical Risk Management 2006:2(4)


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Resistant Prevention & SpreadControl


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Resistance:Key Prevention Strategies

Optimize

Use

Prevent

Transmission

Prevent

Infection

Effective

Diagnosis&

Treatment

PathogenAntimicrobial-ResistantPathogen

Antimicrobial

Resistance

Antimicrobial Use

Infection


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Infection Control Strategies Hand washing Patient screening

Staff screening

Environmental screening

Isolation

rooms/wards Environmental cleaning

Ward closure

Antibiotic prescribing policies

Education


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Vancomycin use vs. Resistance

Years

Situations In Which The Use Of


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1) Serious infections MRSA2) Gr+ ve infection in patients allergic to beta-lactams

3) Severe and potentially life-threatening antibiotic associated colitis,after metronidazole failure

4) Prophylaxis for patients at high risk for endocarditis

5) Prophylaxis for major surgical procedures involving implantation, atinstitutions with a high rate of infections due to MRSA or MRSE

Situations In Which The Use OfVancomycin Appropriate Or Acceptable

CDC. Hospital Infection Control Practices Advisory Committee (HICPAC). 1995.

Recommendations for Preventing the Spread of Vancomycin Resistance.MMWR September22, 1995

Situations Where The Use of


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CDC. Hospital Infection Control Practices Advisory Committee (HICPAC). 1995.

Recommendations for Preventing the Spread of Vancomycin Resistance.MMWR September22, 1995

Situations Where The Use ofVancomycin Should Be Discouraged

1) Routine surgical prophylaxis2) Empiric antimicrobial therapy for a febrile neutropenic patient3) Treatment In response to a single blood culture positive for CNS4) Continued empiric use for presumed infections in patients whose

cultures are negative5) Systemic or local prophylaxis for infection or colonization of indwelling

central or peripheral IV catheters6) Selective decontamination of GIT

7) Eradication of MRSA colonization

8) Primary treatment of antibiotic-associated colitis

9) Routine prophylaxis for very low birth weight (VLBW)

10) Routine prophylaxis for patients on CAPD or HD

11) Treatment of infections caused by MSSA

12) Use of Vancomycin for topical application or irrigation


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Vancomycin is not the 1st drug of choice for Gr+ bacterial infection Infusion related reactions are the most common Vancomycin ADRs

Vancomycin-induced nephrotoxicity and otoxicity are uncommon

Appropriate dosing requires consideration of the site of infection, patientweight, renal function, and concomitant use of high-flux hemodialysis

Routine Vancomycin therapeutic monitoring is not recommended

VRE is a growing problem with limited treatment options

VRE can transfer Vancomycin resistance to other organisms

There is a linear relation between Vancomycin use and VRE

Improving antimicrobial use is a cornerstone of dealing with MDR hospitaland community organisms

Conclusion

MDR, multi-drug resistant


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Question 1

Which one of the following patients is most likely to become

colonized with VRE?

A. A 25-year-old woman admitted to the hospital for ectopic pregnancy

B. A 65-year-old man receiving a 1-week outpatient course of antibiotics forCAP

C. A 40-year-old man on the oncology unit receiving high-dosechemotherapy for AML

D. An 80-year-old woman with CHF who lives alone at home

E. A 50-year-old man admitted to a general medical ward for cellulitis


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Question 2

Which one of the following is the likely portal of entry of VRE

in a 72-year-old woman with multiple blood cultures positive

for VRE?

A. Venous stasis of the lower extremities with intact skinB. Lower respiratory tract

C. Urinary tract

D. Upper respiratory tract

E. Blood transfusion


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Question 3

Which one of the following is the best treatment option for

VRE bacteremia?

A. Linezolid

B. Chloramphenicol

C. Gentamicin

D. Ampicillin

E. Trimethoprim-sulfamethoxazole


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Question 4

Which one of the following is NOT a treatment option for

VRE pneumonia?

A. Linezolid

B. Quinupristin/Dalfopristin

C. Daptomycin

D. Both A and C

E. None of the above


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Question 5

Which one of the following is a bactericidal antibiotic?

A. Quinupristin/Dalfopristin

B. Daptomycin

C. Linezolid

D. Both A and CE. None of the above


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Thanks

Documents

Vancomycin and Vre