Vancomycin & Vancomycin

Resistant Enterococci

Abdullah M. Kharbosh, B.Sc., Pharm

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
Class
 Glycopeptide
MOA
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
Spectrum
 Gram-positive bacteria:
 Streptococci
 Staphylococci
 Enterococcus fecalis
 Clostridium difficile
Adverse Effects
 Red-man syndrome
 Nephrotoxicity
 Ototoxicity
 Other
 Phlebitis
 Thrombocytopenia
 Neutropenia
 Eosinophilia
 Drug fever
 Allergic reactions
Red-Man Syndrome
 What?
 When?
 Why?
 How To Manage?
Nephrotoxicity
 Mississippi Mud
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.
Ototoxicity
 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 with
erythromycin or aminoglycosides
Patients at risk
 Renal impairment
 Receiving high IV doses for prolonged periods
 Having preexisting hearing problems
 Receiving other ototoxic drugs e.g.
 Aminoglycosides
 Cisplatin
 Erythromycin
 Furosemide
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
How Good an Antibiotic is Vancomycin?
 Vancomycin kills bacteria slower than B-lactams

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

Mean duration of Bacteremia

Vancomycin
 MRSA Endocaritis 7 days
Nafcillin
 MSSA Endocaritis 3 days

 Higher mortality with Vancomycin treated patients vs. B-lactams

- Conzalez: CID 29:1171,1999

Dosing
 For appropriate dosing consider:
 Infection site

 Patient weight

 Renal function

 Concomitant high-flux hemodialysis

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

 Determine interval based on creatinine clearance

CrCl (ml/min) Interval

>80 Q 12hr
60-79 Q 18hr
40-59 Q 24hr
20-39 Q 36hr
11-20 Q 48hr
< 10 *
* Give an initial single dose & adjust dose
& interval based upon serum Conc.

Adapted from Matzke, GR, et al. Antimicrob Agents Chemother 1984; 25:433.
Dosing
Condition Dose Duration Trough
PMC 125-250mg PO Q6H 7-10 days NA
Osteomyelitis 15 mg/kg Q12H 4-6 Weeks 15-20
HAP/VAP 15 mg/kg Q12H 14-21 days 15-20
Bacteremia 15 mg/kg Q12H 10-14 days 10-15
Endocarditis 15 mg/kg Q12H 4-6 Weeks 10-15
Meningitis 15mg/kg Q8-12H 10-14 days 15-20

- Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare
associated 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 (Pediatric)
 Usual recommended dose: 40mg/kg/d divided Q6
 Meningitis/Febrile Neutropenia: 60mg/kg/d divided Q6
Dosing (Neonates)
 Usual Recommended Dose: 15mg/kg/dose

Postmenstrual age Postnatal age Dose interval

(Wk) (Day) (Hrs)
< 30 < 15 18
15 or more 12
30-36 < 15 12
15 or more 8
37-44 <8 12
8 8
> 44 All ages 6
Neofax 2007
Uses
 Antibiotic-associated PMC caused by C. difficile
 Enterocolitis caused by S. aureus (including MRSA)
 Skin, soft tissue infections
 Bone and joint infections
 Pneumonia
 Endocarditis
Pseudomembranous Colitis/Enterocolitis

 C. difficile PMC: 125mg PO q6h (higher doses 250-500mg

PO Q6 may be given with ileus or severe disease) x 7-10 d
 Staphylococcal EC: 500-2000 mg PO per day in 3-4 divided
doses x 7-10 d
 PO preparation is not absorbed (ineffective for any infections
other than C. difficile PMC & S. aureus EC)
 IV formulation is not effective for treatment of staphylococcal
EC & PMC caused by C. difficile
 IV Vancomycin can be given orally for C. difficile PMC to
decrease cost ($ 4 vs. $128 per day)
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 treated
with clindamycin, septrin or doxycycline
 For small abscesses and less serious CA-MRSA skin or soft
tissue infections, drainage or local therapy alone may be
effective
 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
Osteomyelitis
 S. aureus is the most common cause of osteomyelitis
 For empiric treatment of osteomyelitis, IV administration of an
antistaphylococcal penicillin such as oxacillin or a first-
generation cephalosporin such as cefazolin would be
appropriate
 Some consultants would use vancomycin until culture
results are available
 If MRSA or CNS is the pathogen: Vancomycin or Linezolid
(alternative) should be used
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 prospective
randomized trials
 Achieves excellent penetration into lung tissues and fluids

 Preferred in renal insufficiency or receiving other

nephrotoxic agents
 But more data are needed
Endocarditis
 Vancomycin is generally the DOC for bacteremia,
endocarditis, & other serious infections caused by MRSA
 Enterococcal endocarditis (HL PNC Resistance/Pen
Allergy)
 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)
Meningitis
 The most commonly responsible organisms for
community-acquired bacterial meningitis in children &
adults are S. pneumoniae (pneumococcus) & N.
meningitidis (≈ 80% of all cases)
 Vancomycin in usual doses may not reach effective levels
in cerebrospinal fluid and clinical response should be
carefully monitored
Therapeutic Drug Monitoring
 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

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

What should be monitored?
 Trough
 Target: 10-15 mcg/ml (Specific:15-20mcg/ml)

 Timing: 30 min pre next dose

Indications for Trough Monitoring
 IV treatment >4 days
 Concomitant Nephrotoxic(S)
 Morbid obesity
 Rapidly changing/Unpredictable renal function
Monitoring Is Not Recommended
 IVtreatment < 4 days
 Oral Vancomycin
Interpretation
 If trough > desired: prolong dosing interval
 If trough < desired: ↑ dose or  dosing interval
Vancomycin Resistant Enterococci
(VRE)
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.

Mechanism of Resistance
Resistance
 Intrinsic Resistance (Its own, non-transferable)
 B-Lactams
 Aminoglycoside (LL)
 Clindamycin
 Erythromycin
 Tetracyclines
 Septrin
Resistance
 Acquired Resistance
 Ampicillin, penicillin (HL)
 Aminoglycosides (HL)
 Quinolones
 Chloramphenicol
 Glycopeptides
 Quinupristin/dalfopristin
 Linezolid
 Daptomycin
Clinical isolation of VRE
 First case: France, 1986
 First case in Saudi Arabia
 In Riyadh Armed Force Hospital, 1993
 Epidemiology
 From late 1980’s – mid 1990’s the rate of
VRE isolates ↑34-fold
 At 2000, ¼ 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.
 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

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, 17:541–547
E.faecalis vs. E.faecium
Resistance Infection Mortality
E. faecalis 3% 85-90% ----
E. faecium 51% 10-15% Higher
ICU vs. Non-ICU
Non-Intensive Care Unit Patients
Intensive Care Unit Patients
30

25
% Resistance

20

15

10

0
89

90

91

92

93

94

95

96

97

98

99

00
19

19

19

19

19

19

19

19

19

19

19

20
Source: National Nosocomial Infections Surveillance (NNIS) System
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 in
Infectious Diseases, Scientific Exchange, Inc.
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)
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.

Colonization
 Colonization usually acquired by susceptible hosts in an
environment with a high rate of patient colonization with
VRE (e.g., intensive care units, oncology units)
 Source of infection
 At an increased risk for VRE infection (Relative risk of 3)

Clinical Infections

Colonized
 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

Anything happen while I was on vacation?
Management of Vancomycin
Resistant Enterococci
Treatment
 Optimal treatment?
 ID consultation
 Follow sensitivities
 Treat only those infected not colonized
Non-Antimicrobial Treatment
 Catheter or device removal
 Abscesses drainage
Approach To Therapy
 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

Teicoplanin
 The cross-resistance shown by many isolates to Teicoplanin
has limited its use as an alternative agent
Linezolid
 Class: Oxazolidinedione
 MOA: Binds P site of 50s ribosomal subunit,
preventing translation initiation
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
Linezolid
 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
 Attractive compare to Vancomycin in patients
 With renal impairment
 Poor or no IV access
 Require outpatient therapy
 Unable to tolerate glycopeptides
Quinupristin–Dalfopristin
 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
Daptomycin
 Class: Cyclic lipopeptide, bactericidal
 MOA: In the presence of Ca2+, Binds membrane  Rapid
depolarization  Cell death
Daptomycin
 Cyclic lipopeptide, bactericidal
 Active 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
Fosfomycin
 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
* 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
Tigecycline
 A semi-synthetic Tetracycline, static, broad-spectrum
 Approved for:
 Complicated SSSI (MRSA & Vancomycin-susceptible E. faecalis)
 Complicated intra-abdominal infections
 In intra-abdominal infections/complicated SSSI (more
convenient Q12 dosing compared to imipenem/cilastin
and piperacillin/tazobactam
 Off-label use: VRE Non-life threatening SSSI
 Can be used, but because it has a very broad spectrum
of activity (reserved for patients unable to take other
drugs or with documented polymicrobial coinfection
 ADRs:Nausea & vomiting may occur in up to 1/3 of patients
Nitrofurantoin
 Due to its ability to achieve high urinary Con. has been shown
to 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 <30 mL/min because: ↑ blood Conc.
are associated with hepatic, pulmonary,& hematologic
toxicities
 Near term or during labor or delivery use: can cause hemolytic
anemia in the newborn
 Glycopeptides Vs. Available Alternatives
Recently Introduced Into The Market

Vanco Teicop linez Q/D Dapto Tigecy

IV/PO both N* N Y N N N
available
Outpatient N Y Y ? ? ?
Need of TDM Y N N Y N N
Frequency of Q12 to Q24 Q24 Q12 Q24 Q24 Q12
ADM

Abbreviations
Y: Yes, N: No
TDM: Therapeutic Drug Monitoring
ADM: Administration
Note: *indication restricted to the management of Clostridium difficile-associated diarrhea.

Therapeutics and Clinical Risk Management 2006:2(4)

Resistant Prevention & Spread
Control
Resistance:Key Prevention Strategies

Antimicrobial-Resistant
Pathogen Pathogen
Prevent Prevent
Transmission Infection

Antimicrobial Infection
Resistance
Effective
Diagnosis
Optimize &
Use Treatment

Antimicrobial Use
Infection Control Strategies
 Hand washing
 Patient screening
 Staff screening
 Environmental screening
 Isolation – rooms/wards
 Environmental cleaning
 Ward closure
 Antibiotic prescribing policies
 Education
Vancomycin use vs. Resistance

Years
 Situations In Which The Use Of
Vancomycin Appropriate Or Acceptable
1) Serious infections MRSA
2) 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, at
institutions with a high rate of infections due to MRSA or MRSE

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

Recommendations for Preventing the Spread of Vancomycin Resistance. MMWR September 22, 1995
 Situations Where The Use of
Vancomycin Should Be Discouraged
1) Routine surgical prophylaxis
2) Empiric antimicrobial therapy for a febrile neutropenic patient
3) Treatment In response to a single blood culture positive for CNS
4) Continued empiric use for presumed infections in patients whose
cultures are negative
5) Systemic or local prophylaxis for infection or colonization of indwelling
central or peripheral IV catheters
6) 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
CDC. Hospital Infection Control Practices Advisory Committee (HICPAC). 1995.
Recommendations for Preventing the Spread of Vancomycin Resistance. MMWR September 22, 1995
Conclusion
 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, patient
weight, 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 hospital
and community organisms

MDR, multi-drug resistant

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 for
CAP
C. A 40-year-old man on the oncology unit receiving high-dose
chemotherapy 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
 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 skin
B. Lower respiratory tract
C. Urinary tract
D. Upper respiratory tract
E. Blood transfusion
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
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
Question 5
Which one of the following is a bactericidal antibiotic?
A. Quinupristin/Dalfopristin
B. Daptomycin
C. Linezolid
D. Both A and C
E. None of the above
Thanks