Good

Morning
 MRSA

Prevention & Control

 If use penicillin, use enough

The time may come when penicillin can be bought by

anyone in the shops.

Then there is the danger that the ignorant man may

easily underdose himself and by exposing his microbes
to non-lethal quantities of the drug make them
resistant…..

not enough to kill the

streptococci but enough to educate them to resist
penicillin…
but enough to fail the penicillin
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.pdf
From Golden era of Antibiotics to era of
Superbugs

Shift from Golden, the halcyon years when most of the antibiotics were discovered; to the lean
years, the low point of new antibiotic discovery and development; to the era of Superbugs

Julian Davies et al, Origins and Evolution of Antibiotic Resistance, Microbiol. Mol. Biol. Rev.September 2010 vol. 74 no. 3417-433
Superbugs and Super-resistance

Bacterial pathogens associated

with epidemics of human disease
have evolved into multidrug -
resistant (MDR) forms

Julian Davies et al, Origins and Evolution of Antibiotic Resistance, Microbiol. Mol. Biol. Rev.September 2010 vol. 74 no. 3417-433 CID 2011;53(Suppl 1):S8
Drying Antibiotic Pipeline a big challenge….

IDSA supported a proGRAM called the “10x20 initiative” to develop new systemic antibacterial
drugs within 2020…. Especially against the “ESKAPE” pathogens
 Why Are ICU’s Vulnerable??

Ideal Environment for generation of MDR Organisms

Patient Factors:
Intensive Environment Care:
1. Impaired Immune Responses
1. Haven for resistant bacteria to facilitate cross
2. Invasive devises as conduits for infection
transmission
3. Underlying Medical condition
2. In immediate life threatening situations – Difficult
4. Frequent Hospital Admission
to maintain Aseptic conditions
5. Increased risk of colonized infections
3. Over crowding , Over Staffing & Transfer of
patients between ICU’s
4. Antimicrobial Use

JC Hatcher, R Dhillon, B Azadian, JICS Volume 13, Number 4, October 2012

 MDR BUGS IN THE ICU

MDR Acinetobacter Pseudomonas Klebsiella MRSA

Commensal causing infection through Colonization
Pathogenesis of Nasal Colonization
S. aureus reaches the
nose

Binds to nasal
epithelium

Overcomes Host
• Adherence to Defenses
keratinized S. aureus propagates
• Hand carriage • epithelial cells, mucosa • Dysregulation of
• Nose picking or apocrine sweat innate humoral
• Airborne transmission glands factors
• Environmental factors • Binding to specific • Inability of nasal Nasal Colonization
receptors via adhesions antimicrobial
- ClfB peptides to clear S.
- SasG aureus
• Resistance of S. • Evolution of clonal complexes
aureus

Host Defenses
Colonization Infection
Breached

C. L. Abad et al. Does the Nose Know? An Update on MRSA Decolonization Strategies. Curr Infect Dis Rep (2013) 15:455–464
 Gram Positive Organisms
 Staphylococcus

 Coagulase Negative Staphylococcus (CONS)

 Staphylococcus aureus

 Streptococcus

 S. pneumoniae, bovis, viridans

 Enterococcus

 E. faecalis, faecium
Gm +ve pathogens & various body systems
Cardiovascular
Enterococci 8.7
S Aureus 8.6
CONS 54.2

ENT Infection
S Pneumoniae 0.5
Enterococci 4.9
S Aureus 13
CONS 15
Surgical Site S aureus and CONS are observed to
Other Gram+ 9.2 be amongst the most common offending
8.8
S Aureus
1
CONS 11.7
Pathogens
Enterococci 17.1
Pneumonia
Enterococci 1.8
S Pneumoniae 1.6
S Aureus 17

Primary Blood Stream

S Pneumoniae 0.4
Enterococci 11
S Aureus 12
CONS 39

0 10 20 30 40 50 60

Richards et al seminars in respiratory and critical care medicine 2003;24(1):1-22

 Gram positive infections are increasing
Results of a 12-year study (1980–1992) involving 260834 pts with nosocomial infections

 Significant increase in incidence of infection from Gram + organism, rising from

48% to 52%

54%

42%

1981-1983 1990-92

 Blood cultures:
• Gram-positive cocci isolates increased x 2.5
• Gram-negative isolates unaltered

Pittet et al. Arch Intern Med 1995;155:1177–1184

 Gram +ve infections are increasing
Gram Positive : common offending pathogen in Sepsis
3,25,000
Gram-negative bacteria

Gram-positive bacteria
N o . O f C a s e s o f S e p s is

1,50,000
Fungi

75,000

25,000

15,000

10,000

5,000

0
1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001
 Gm +ve infection in Indian settings
Rank order of pathogens in skin and soft tissue infections
40 38.05

35

S Aureus, E Coli, Pseudomonas were

30
found to be the Top 3 Pathogens
covering over 67% of infections
25

20
17.39

15
11.82
10.16
10
6.72
5.5
5
2.87 2.8 2.26 2.19
0.18
0.03
0
S Aureus E Coli 1 Pseudomonas spp
Acinetobactor spp Klebsiella Coag Neg Staph
Citrobacter spp %
Enterobacter spp Proteus spp
Enterococcus spp Beta hemolytic Strep Streptococcus Pneumoniae
S Mohanty et al. Indian J of Med Sci 2004;58(1):10-16
 Prevalence Of Staphylococci
Staphylococci (Staph aureus and 47 % to 52% by
CONS) and enterococci are now Staphylococci
reported causative organisms in
47% to 52% of nosocomial
blood stream infections

Overall responsible for 30% European intensive units

of all infections across USA attribute 50% of all infections
to Staphylococci

30% across USA 50% in Europe

“Gram positive infections have become the leading cause of

infection in patients with cancer and account for 60–70 % of all
microbiologically documented bacterial infections.”

Drugs 1996 ; 51 (suppl 1) : 6 -1 2

Increasing Prevalence Of Staphylococci
Studies has shown infection from staphylococci to be as high as 23.3% in LRTI 1

Staphylococci
(23.3%)

Blood stream infection with Infection Rates with CONS has

Staphylococci aureus increased increased from 10.6% to 12.8%
from 22.9% in 1997 to 28.7% in in 2001.
2001 2

28.7%
22.9%
12.8%
10.6%

1997 2001 1997 2001

1) Diag Microbiol Infect Dis 2002; 44 (3) : 301 – 311
2) Semin Respir Crit care Med 2003 : 24 (1) : 121 - 134
 What is MRSA ?
 Gram-positive spherical shaped organism arranged in clusters

 Resistant to Methicillin. So resistant to all Penicillins & Cephalosporins. They are

variably resistant to other antibiotics

 Opportunistic pathogen. Can cause boils, abscesses, impetigo, osteomyelitis, pneumonia,

meningitis, septicemia

 No way different from ordinary Staph. aureus strain

 Types of methicillin resistance

 β-lactamase resistance

 Alteration in PBP’s especially PBP2a (mec-gene).

Has low affinity to pencillinase resistant synthetic penicillins

 Tolerance
 MRSA :Country-wise Incidence1
Greece 72/137
Portugal 94/180
Italy 279/687
Ireland 202/514
Spain 127/348
Belgium 67/305
Luxembourg 5/40
Germany 57/660
Finland 9/250
Netherlands 10/1178
Sweden 14/1175
Denmark 0/502 MRSA isolates/No. isolates
Iceland 0/41
0 10 20 30 40 50 60
Percentage MRSA

India has recorded MRSA incidence as 38.56% 2

1.Wise R J of Antimicrob Chemother 2003: 51, Suppl. S2, ii5–ii7
2.S Mohanty et al. Indian J of Med Sci 2004;58(1):10-16.
 MRSA: Incidence in India
Results:
Pilot program of
MRSA surveillance in
INDIA4

• Total no. of test samples:

13,610
• Total Staphylococcal isolates:
739
• Study period: 6 months
• Study centres: AIIMS, Delhi,
P. D. Hinduja-Mumbai and
Kidwai Memorial Institute of
Oncology-Bangalore

4. Mehta A A et al, J Postgrad Med 1996;42:1-3

 Risk factors for MRSA

 Prolonged hospital stay

 Prolonged use of antibiotics

 Extremes of age

 Immuno-compromised patients

 Surgical implants, prosthesis, artificial heart valves

 Indwelling central line catheters or urinary catheters for prolonged period

 Increasing Incidence of MRSA
3000 80

70
S. aureus Infections in
60
Intensive Care Units is most
No. of infections

common but now MRSA

Percentage of
infections
2000
50 incidence has risen by
double and that is a concern
40

30
1000

20

10

0 No.of Infections
0
Percent of Infections resistant to methicillin
1987 1989 1991 1993 1995 1997
1988 1990 1992 1994 Percent of methicillin-resistant infections
1996
sensitive only to vancomycin
Year

Both Gram positive infections and infections due to MRSA are on the
rise. Both have increased by almost 100% over the last decade

Lowy F NEJM 1998;339(8):520-532

Increasing incidence in ICU & Non-ICU nosocomial infections
Nosocomial Methicillin-Resistant Staphylococcus aureus (MRSA) Infections

50

40
Prevalence (%)

30

20
ICU
10 Non-ICU

0
1989 1990 1991 1992 1993 1994 1995 1996 1997
(Year)
Fridkin et al. Clin Chest Med.1999;20:303.
 Mortality Associated with MRSA

50
MRSA

40 MSSA
36%

30 p<0.001 29%

20 23% p<0.001

10 12%

0
1980-2000 a 1990-2000 b

n=3963 n=2209

Mortality associated with MRSA is significantly higher as compared to

MSSA. Hence MRSA should receive aggressive attention and treatment.

Segreti J et al Clin Microbiol Infect 2005; 11 (Suppl. 3): 29–35

MRSA management

 Prevention?

 Treatment?
Chain of Transmission of Infection

Transmission occurs when the agent, in

the reservoir, exits the reservoir through a
portal of exit, travels via a mode of
transmission and gains entry through a
portal of entry to another susceptible host
in the ICU.

Routine Practices and Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Advisory Committee (PIDAC)
 Breaking the Chain of Transmission

Transmission may be interrupted when:

Controls in your Hand to prevent the chain of
• the agent is eliminated or inactivated or cannot
Transmission:
exit the reservoir
1. Portals of Entry through Hand hygiene, use of
• portals of exit are contained through safe
PPE (gloves, masks, gowns etc)
practices
2. Mode of transmission through hand hygiene
• transmission between objects or people does not
and PPE
occur due to barriers and/or safe practices
3. Portals of exit through proper hand hygiene
• portals of entry are protected
• hosts are not susceptible

Routine Practices & Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Adviso
Committee (PIDAC)
Practices to break the chain of Transmission

Routine Practices

Additional Practices

Routine Practices and Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Advisory Committee (PIDAC)
 Routine Practices
 Routine Practices are based on the principle that all patients/residents are potentially infectious.

 Routine Practices to be adopted by each one in the health care setting & into the daily practice of
each health care provider to protect both patients & providers

Routine Practices and Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Advisory Committee (PIDAC)
Routine Practices where you can make a Difference
Because every little thing you do, will make a difference
Risk Assessment Respiratory etiquettes

Personal protective equipment

Hand Hygiene
 Risk Assessment

Use appropriate controls and PPE to protect the patient and yourself where a risk of
transmission of infection based on the risk assessment (If the patient has uncontained diarrhea,
PPE such as gloves and a gown while changing the bed sheets, to prevent contamination of hands
and clothing)

Routine Practices and Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Advisory Committee (PIDAC)
Hand Hygiene

WHO“My Five Moments for Hand Hygiene”Concept (World Health Organization)

Hand rub vs Hand Wash

WHO“My Five Moments for Hand Hygiene”Concept (World Health Organization)

 Personal Protective Equipment

 PPE is used to prevent transmission of infectious agents from

patient-to-staff, also prevent transmission from patient-to-patient,
staff-to-patient and staff-to-staff

 Gloves

 Gowns

 Masks
 Respiratory Etiquettes
 Respiratory etiquettes: Involve the personal
practice that prevent spread of micro organism
that cause respiratory infection
 Avoid visits ill with acute respiratory infection
 avoidance measures that minimize contact with droplets
when coughing or sneezing, such as:
 turning the head away from others
 maintaining a two-metre separation from others
 covering the nose and mouth with tissue
 immediate disposal of tissues into waste after use
 immediate hand hygiene after disposal of tissues.

Routine Practices and Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Advisory Committee (PIDAC)
Respiratory Etiquettes
 Additional Precautions

 Visitors should be kept minimal

 Visitors must receive education about hand hygiene

 Visitors must wear PPE

 In addition to routine hand hygiene, ensure hand hygiene by the patient

Routine Practices and Additional Precautions In All Health Care Settings, 3rd edition Provincial Infectious Diseases Advisory Committee (PIDAC)
 Current recommendations - MRSA control

 Contact precautions

 Handwashing

 Gloves, gown/apron

 Screening

 Isolation
 Glycopeptides

 Vancomycin

 Teicoplanin

 Telavancin

 Ramoplanin

 Bleomycin
 Glycopeptides

 Glycopeptides inhibit cell wall synthesis

 Glycopeptides bind to D-ala subunit on peptide chains to inhibit transglycosylase activity

 Result: no new subunits added to the existing cell wall , wall weakened, lysis occurs

 Glycopeptides have time-dependant kill kinetics

 Glycopeptide - Spectrum of activity

Activity specific to gram-positives; gram-negatives naturally resistant due

to  permeability into outer membrane

S aureus S. pneumoniae
S. epidermidis (CNS) S. pyogenes
S. saphrophyticus S. viridans
S. haemolyticus E. faecalis

Corynebacterium spp
Clostridium spp
Listeria spp
 Clinical use of Glycopeptides
Glycopeptides are indicated for a variety of infections caused by gram-
positive bacteria including:
1. Endocarditis
2. Bacteraemia
3. Septicaemia
4. Osteomyelitis
5. Skin and soft-tissue infections
6. Pneumonia
7. Urinary tract infections
8. Line infections
9. Infections involving prosthetic joints and valves
10. Gram-positive infections in penicillin-allergic patients.
 Vancomycin Toxicity

Red-man syndrome

Other sensitivity reactions are: anaphylaxis and skin reactions.

Vancomycin also causes nephro- and ototoxicity, especially when blood and serum levels
are high.
Serum monitoring & monitoring RFT is necessary.

Has a complicated dose adjustment for patients with renal impairment.

“Red-man syndrome” is an anaphylactoid reaction causing:
1. Hypotension
2. Throbbing pain in back muscles

3. Extreme flushing of the skin of the neck and

shoulders

4. Tachycardia.
 Teicoplanin

 Active against penicillins and cephalosporin resistant gram positive organisms 1

 Longer ½ life & higher drugs levels above MIC for 24 hrs, can be given OD1

 Can be given by IV /IM route, unlike vancomycin

 Teicoplanin is 2 to 4 times more active than Vancomycin against susceptible strains 3

 Effective against Vancomycin resistant strains like Van B, Van C, Van D. Not effective against
Van A type 3

1) Eur J Hematol 1993 ; 51 (54) : 10 –13 2) The use of Antibiotics. 5th Ed. Pg 763 – 791;;
3) Antibiotics & Chemotherapy 2003, 8th Ed. 300 - 304
 Teicoplanin v/s Vancomycin Risk of
Nephrotoxicity
70
60 56
47 50
50
38 40
40
30 25
20
8 9.5
10
0
Davey and Chow et al. Charbonneau et Cheng-Yi Liu et
Williams al. al.

Teicoplanin Vancomycin

Charbonneau P, et al. Intensive Care Med 1994; 20: S35-S42.Chow AW et al. Eur J Haemat 1993; 51 (Suppl. 54): 18-24.
Davey PG, Willaims AH. J antimicrob Chemother 1991; 27 (Suppl. B): 69-73.
Cheng-Yi Liu, et al. Clin Drug Invest 1996; 12 (2): 80-87.
 Linezolid
 Bacteriostatic

 Spectrum: Gram Positive

 Dose: 600 mg IV/PO Q12h

 Concentrates well in the lung

 Side Effects: thrombocytopenia

 MAO inhibition : serotonin syndrome, hypertensive crisis with dopaminergic agents if

used together in ICU.
 Gram positive agents
 Already

 Vancomycin,Teicoplanin

 Linezolid, Qunipristine+Dalfopristine , tigecycline,

 Future

 Daptomycin, oritavancin, Telavancin, Dalbavencin

 Iclaprim

 Anti MRSA cephalosporins

The Glycopeptide Creep & Challenge in dosing

 No of Susceptible isolates as per the CLSI guidelines

gradually decreasing over the 5 year Period

 The Average MIC from .75mcg/ml has gone up to 1

mcg/ml

 Hence to achieve target trough Concentrations is

getting more difficult

Sourced from. Gould IM, 2008, International Journal of antimicrobial Agents.

 With Absence of new antibiotics in
the pipelines strategies as dose
optimization with current agents
become important

“ ONE DOSE FITS ALL” is problematic”

PK/PD translates the Microbiological to Clinical outcome

Peak Conc PK/PD

variability

Expected
MIC PK/PD

MIC Variable
PK/PD

Extreme variability in PKs and PD can lead to suboptimal outcomes

Rello J, Restrepo M.I. Sepsis. New Strategies for Management. 2008

 Selection of Resistance

The reduction of appropriate antibiotic

therapy selects MDR organism acquisition
and increases resistance selection

Risks for multidrug-resistant pathogens in the ICU ;Ignacio Martı´n-Loechesa,b, Emili Diazb, and Jordi Valle´sb, Volume 20 Number 5 October 2014
The probability of (+) clinical outcome associated with increasing levels of PK/PD ratio were
markedly different for higher & lower levels of disease severity levels

DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current β-Lactam Antibiotic Doses Sufficient for Critically Ill Patients? The DALI Study • CID
 Conclusion
 Hospitalization period in an ICU, presence of patients colonized with MRSA in the same ICU at the
same time, previous antibiotic use, & central venous catheter insertion are independent risk factors for
ICU-acquired MRSA infection

 Detection of these factors helps us to decrease the rate of MRSA infections in the ICUs

 If the strain is MRSA , stop using all types of penicillins and cephalosporins irrespective of their in
vitro sensitivity

 Quinolone resistance is very high among MRSA

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Backup Slides
ARE we Entering the ERA of PDR??

1. S Dewan, T Sahoo, N Chandra, A Varma Fortis Escorts Heart Institute, New

Delhi, India Critical Care 2013, 17(Suppl 2):P76 (doi: 10.1186/cc12014)
Colonization and its role
 The infections can cause due to
o impaired host defense
o access of pathogenic bacteria
in sufficient numbers to the
lower respiratory tract
o virulence of the organism
 Infections are caused either due
to an endogenous or exogenous
source (figure 2)

FiEndogenous and exogenous sources of microorganisms

causing hospital-acquired pneumonia (HAP) and ventilator-
associated pneumonia (VAP).
 ICUs are known to harbor multidrug-resistant pathogens:

Optimized dosing that minimizes the evolution of such pathogens should be considered a method
to improve patient and health system outcomes

1. For 50% fT>MIC &100%fT>MIC a high PK/PD ratio was associated

with higher likelihood of a positive clinical outcome.

2. For BSI, a significant association was clearly present with increasing

antibiotic concentrations at 50% of the dosing interval .

3. The study shows that mid dose and trough β-lactam concentrations
vary widely and PK/PD targets are highly inconsistent.
Hence :

“ ONE DOSE FITS ALL” is therefore shown here to be problematic”.

Consequences of higher Doses of Vancomycin
2439 patients 20 Studies 11 years

Increased Mortality Treatment failure

Gram Positive Organisms: Common
Infections
 Pneumonia
 Community-acquired
 Hospital/Ventilator-associated pneumonia
 Bloodstream/Catheter infections
 Skin and Soft Tissue Infections
 Osteomyelitis
 Surgical Infections
 Others
Most common pathogens associated with nosocomial infection
among patients in ICU’s, January 1989–July 1998

40
Bloodstream infection
Pneumonia
The most common
35
Percentage by site of infection

Urinary tract infection pathogen for BSI and

30 Surgical site infection pneumonia in ICU’s
was CONs and S
25 Aureus
20

15

10
i

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cc
co
lo
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ap

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at

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Wise R . J Antimicrob Chemother 2003: 51, Suppl. S2, ii5–ii7

 Types of MRSA resistance
Character β-lactamase Intrinsic Tolerance
mediated
MIC Very high High Normal
MBC Very high High Normal
Limited to β-lactam Yes Yes No
Group
Phenotypic expression 99.9% 10-5 10-2
Rate of growth Rapid Slow Rapid
Stability of resistance Stable Stable Unstable
Occurrence in 80-90% 1-8% Up to 40%
hospitals
Clinical importance Yes Yes Yes
Phage type Many Few Many
Protein A Common Low Not tested
Overview
 MRSA is a major pathogen that causes severe morbidity and mortality in
many hospitals worldwide
 MRSA strains are endemic in many American & European hospitals &
account for 29% to 35% of all clinical isolates
 20% to 40% of nosocomial S. aureus infections in endemic hospitals are
methicillin resistant
 ICUs are high-risk areas for MRSA infections
 In 1992, MRSA accounted for 57% of all ICU-acquired S aureus infections
in Europe

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Discussion
 Risk factors associated with hospital-acquired MRSA infection are
established as
 advanced age
 male sex
 previous hospitalization
 length of hospitalization
 stay in an ICU
 chronic medical illness
 prior antibiotic therapy
 exposure to colonized or infected patient
 presence of indwelling devices

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Multivariate analysis of risk factors for ICU-
acquired MRSA infections(Table-2)

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Risk Factors for ICU-acquired
MRSA
Surgical ICU
 MRSA infections were significantly higher in surgical ICUs in this study
 Doing more invasive procedures & using antibiotics inappropriately for
preoperative prophylaxis in surgical ICUs may explain this fact
 In several studies, wound infection was detected as the most frequent
infection because of MRSA, and surgery has been reported to be a risk
factor for MRSA infection

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Primary Bloodstream Infection
 The most frequent MRSA infection was primary bloodstream infection
 This shows that, in ICUs, invasive procedures are practiced excessively, &
it was supported by the finding of central venous catheter insertion & total
parenteral nutrition as risk factors
 Primary bloodstream infection is one of the major staphylococcal
infections

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Hospital Reservoir of MRSA
 Infected & colonized pts, patient carriers, staff carriers, & possibly,
hospital invironment
 Nose is the most frequent carriage site for S aureus
 It was found that 57% of infected patients had nasal MRSA colonization,
& nasal colonization was a significant risk factor for MRSA infection
 Carriage of S aureus is a risk factor for development of infections in
various settings

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Hospital Reservoir of MRSA
 In study by Coello et al, > 50% of MRSA-infected patients also yielded
MRSA from 1 or more carriage sites, & treatment of carriers coincided
with reduction in number of newly infected patients, & control of large
hospital outbreak affected > 900 patients

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Hospital Reservoir of MRSA
 Pujol et al showed that nasal MRSA carriers had a very high risk of
developing MRSA bacteremia in ICU pts
 Mest et al found a relationship b/w nasal colonization & postoperative
MRSA infection in surgical ICUs
 Authors concluded that autoinfection from nasal carriage or cross infection
seemed to be the most common mode of acquisition of MRSA infections

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Hospital Reservoir of MRSA
 Blok H et al suggested that mobile reservoirs, such as personnel or medical
devices, play an important role
 Health care workers (HCWs) acquired MRSA after caring for MRSA-
positive patients, despite isolation precautions
 Therefore, HCWs have a critical role in transmission of MRSA from one
patient to another

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
Other Factors
 Length of hospitalization, invasive procedures, & previous antibiotic use
are known risk factors for acquisition of infections with multidrug-resistant
bacteria
 Hospitalization period in an ICU, mechanical ventilation, central venous
catheter insertion, total parenteral nutrition, and previous antibiotic use were
risk factors for ICU-acquired MRSA infection
 Hospitalization period in an ICU, central venous catheter insertion, & previous
antibiotic use were independent risk factors & they increased risk of MRSA
infection 1, 1.8, & 2.3 times, respectively

Risk factors for ICU-acquired MRSA Am J Infect Control 2006 34(1) pp 1-5
 Antibiotics for Gram Positive Organisms
Oxacillin Teicoplanin Vancomycin Daptomycin Linezol Tigecycline Q/S
id

OSSA YES YES YES YES YES YES YES

MRSA NO YES YES YES YES YES YES

Entero NO YES YES YES YES YES Only

coccus faeci
um

VRE NO NO NO YES YES YES Only

faeci
um
Antibiotics for MRSA
 Vancomycin Toxicity

Vancomycin needs to be given in a highly acidic form in

order to remain active.

This causes severe local pain and often thrombophlebitis.

“Red-man syndrome” is an adverse effect caused by

Vancomycin itself. It is associated with the rapid infusion of
Vancomycin i.e. when given over a period of less than 60
minutes.
Teicoplanin
Role of Teicoplanin
 Hospital acquired infections
Reasons for Mortality
60
52.1
50
42
40 Adequate
Antimicrobial Therapy
30
Inadequate
17.7 23.5 Antimicrobial Therapy
20

10 Hospital Mortality (%)

0
Infection All Cause
Related

Höffken G, et al. Chest 2002; 122: 2183 - 96

 Teicoplanin in CR-BSI

Empiric antimicrobial treatment

should include a glycopeptide
(Teicoplanin or Vancomycin) as
staphylococci are the most
frequent cause of Catheter Related
Infections.
Rodriguez-Bano J. Clin Microbiol Infect 2002; 8: 275-81
 Teicoplanin in Nosocomial Pneumonia

Glycopeptide antibiotics teicoplanin

and Vancomycin form the mainstay
against Nosocomial Pneumonia
attributable to MRSA.
Hunter J D Postgrad Med J 2006; 82: 172-178
Teicoplanin v/s Vancomycin in Febrile
Neutropenia
 Teicoplanin in Infective Endocarditis

European studies of teicoplanin in endocarditis 1

Study No. of Success Comments on

patients Rates Molecule
enrolled

Presterl et
al
26 ( all
monotherapy) 92% Teicoplanin
effective as a
single agent
therapy

Cruciani et 13 (9 92% = Teicoplanin is

al monotherapy) eradication effective
83% =
clinical
success

The dose (s) of teicoplanin, duration of therapy and adverse events varied in the above studies.
Doses of teicoplanin ranged from 1.5 to 30 mg/kg. Duration of therapy ranged from 3 to 125 days. Adverse events ranged from 13% to 35%.
Pittet D et al, J of Infect 1998; 37: 127-135
Teicoplanin in Orthopaedic Prophylaxis

Success rates at
3 months 12 months
Teicoplanin
(400 mg i.v. 99.2 99.7%
bolus at time
of
%
anesthesia)2

Randomised multicentric study in 12 centers in Italy comparing Teicoplanin to Cefazolin 860 patients enrolled :
846 (427 : teicoplanin , 424 cefazolin) were evaluable for safety and 826 for efficacy

CDC : Centers for Disease Control and Prevention

1.Soriano A. et al , Eur J Clin Microbiol Infect Dis 2006; 25: 35-38
2. Periti P et al Eur J Clin Microbiol Infect Dis. 1999 Feb ; 18(2) :113-9
 Teicoplanin
 Teicoplanin shows synergistic action when combined with fluoroquinolones or
broad spectrum cephalosporins. 1
 Teicoplanin is more effective against streptococci and especially against
enterococci as compare to vancomycin 3
 Owing to the acidic nature of solutions, vancomycin is incompatible In-vitro
with various agents, including B-lactams, certain antibiotics, aminophylline and
Heparins 2
 Vancomycin has a short elimination & plasma half life hence it is given as either
BD / QDS 2

1) Diagn Microbiol Infect Dis 1997 ; 29 (2) : 87 – 94 2) Antibiotics & Chemotherapy 2003, 8th Ed. 300 – 304
3) The use of Antibiotics. 5th Ed. Pg 763 - 791
MAO inhibition and drug interactions with Linezolid

Tyramine rich foods Adrenergic , dopaminergic

(cheese, beer etc.) agents
Serotonergic agents

Serotonin Norepinephrine

MAO
Serotonin Hypertensive
syndrome crisis

NE metabolites
Serotonin metabolites
Linezolid
 Linezolid resistance in therapy
Enterococci
Scatter of reports
Under-dosage, difficult sites, long Rx
One report of spread in a unit
MRSA
3 reports: peritoneal dialysis one empyema
Antimicrobial Resistance in Nosocomial Pathogens

Drug/Pathogen Resistance (%)

Vancomycin/enterococci 24.7
Methicillin/S. aureus 53.5
Methicillin/CNS 88.2
3rd Ceph/E. coli 3.9
3rd Ceph/K. pneumoniae 10.4
Imipenem/P. aeruginosa 16.4
Quinolone/P. aeruginosa 23.0
3rd Ceph/P. aeruginosa 20.6
3rd Ceph/Enterobacter spp. 33.1
 Classes of Glycopeptide Resistance
Level of Resistance
Phenotype Vancomycin Teicoplanin How Developed
VanA high high acquired/transferable;
plasmid-mediated
VanB moderate susceptible acquired/transferable;
to high conjugation
VanC low susceptible intrinsic/non-transferable;
chromosomally-mediated
VanD moderate low or susceptible unknown
 Increasing Vancomycin resistance
Nosocomial Enterococci Infections
Resistant to Vancomycin

ICU
Non-ICU
25

20
% Resistance
15

10

0
1989 1990 1991 1992 1993 1994 1995 1996 1997
Year

*NNIS 1989-1997.
Fridkin SK, Gaynes RP. Clinics in Chest Medicine. 1999.
 Antibacterial Drugs in Development

Potential Class
Drug Class Target Mechanism Route Adverse Events

Linezolid Oxazolidinone Ribosome A Site Static Oral/IV Marrow Suppression

(Approved)

Quinupristin / Streptogramin Ribosome Static IV Musculoskeletal Pain,

dalfopristin Phlebitis
(Approved)

Oritavancin Glycopeptide Cell Wall Cidal IV Hypersensitivity

(Phase 2/3) D-Ala D-Lac

Daptomycin Lipopeptide Cell Membrane Cidal IV Skeletal Muscle

(Phase 3)

Tigecycline Tetracycline Ribosome Static IV GI Intolerance

(Phase 2/3)
 Newer Therapies
 Daptomycin
 Telavancin
 Tigecycline
 Quinupristin/Dalfopristin
 Oritavancin
 Dalbavancin
 RWJ-52248: anti-MRSA cephalosporin
 Iclaprim (AR-100)
 Newer Therapies:
Long half life glycopeptides

Oritavancin Dalbavancin
Spectrum G+ve, inc. VRE G+ve, not VRE
Mechanism Classical + Classical
Bactericidal? Rapidly Slowly
Half line (days) 7-10 7
 Newer Therapies :
Oritavancin

MIC90, mg/L
Oritavancin Vancomycin Teicoplanin
MSSA 4 2 4
MRSA 4 2 4
VSE 0.5 2 0.5
VRE 1 >256 4 - 64
S. pneumo <0.03 0.12 <0.03
 Newer Therapies: Telavancin

 Glycopeptide
 Once a day therapy
 Phase 3 : Skin and soft tissue infections
 Newer Therapies: Tigecycline

 Derivative of minocycline
 Similar mechanism of action
 Broader activity (esp against resistant organism)
 Spectrum: Gram Positive, Gram Negative & anaerobic coverage
 Dose: 100 mg IV LD; 50 mg IV Q12h
 Side effects: N/V (nausea,vomiting) (decreased after 48 hours)
 MIC90s of Tigecycline

Tige- Mino- Tetra-

S. aureus 0.5 1 >32
Enterococci 0.5 8 >32
Pneumococci 0.12 4 32
E. coli minoR 0.5 16 >32
E. coli minoS 0.5 0.5 2
P. aeruginosa 16 8 32
B. fragilis 2 0.5 4

Petersen et al., 1999

 Newer therapies :
Quinupristin/Dalfopristin (Synercid)
 Unrelated streptogramin A (dalfopristin) and B (quinupristin) mixture
 Act synergistically on the ribosome
 MICs 0.5 -2 mg/L for most Gram+ve , G-ves Resistant
 Licensed for nosocomial pneumonia, skin & soft tissue infection, E. faecium
infection
 Need central line to avoid venous side-effects
 10% rates of myalgia & arthralgia
 Newer therapies
RWJ-52248: anti-MRSA cephalosporin
MIC90 (mg/L)
MSSA 0.5-1
MRSA 2
E. faecium 8
E. faecalis 0.25-0.5
Pneumo’s PenS 0.015
Pneumo’s PenI 0.25
Pneumo’s PenR 0.5
 Newer Therapies
Iclaprim (AR-100)
 Dihydrofolate reductase inhibitor
 Anti G +ve & G-ve
NH2  8 x more active than trimethoprim
O vs. G+ve’s, inc. pneumococci
N
 Overcomes low level trimethoprim R
in most G+ve’s not G-ve’s
N
H2N OCH3
OCH3