Management of MRSA NP

Slide Reference
Pneumonia
 Definitions
• Pneumonia was defined in the 2005 IDSA document as the presence of
“new lung infiltrate plus clinical evidence that the infiltrate is of an
infectious origin, which include the new onset of fever, purulent
sputum, leukocytosis, and decline in oxygenation.”1
• Hospital-acquired pneumonia (HAP) is defined as a pneumonia not
incubating at the time of hospital admission and occurring 48 hours or more
after admission.
• Ventilator-associated pneumonia (VAP) is defined as a pneumonia
occurring >48 hours after endotracheal intubation.1
• Healthcare-associated pneumonia includes patients who was hospitalized
in an acute care hospital for two or more days within 90 days of the infection;
resided in a nursing home or long-term care facility; received recent
intravenous antibiotic therapy, chemotherapy, or wound care within the past
30 days of the current infection; or attended a hospital or hemodialysis
clinic.2
– Concept removed in 2016 IDSA guidelines2
1. ATS, IDSA Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-
associated pneumonia Am J Respir Crit Care Med 2005; 171:388–416.
2. Kalil, AC, et al. Clin Infect Dis. (2016) doi: 10.1093/cid/ciw353.
Prevalence of HAP & VAP
• VAP incidence was higher in small hospitals
(2.1) than medium (0.85) or large (0.69)
hospitals (P = .03) despite a lower VUR in
small hospitals (0.29 vs 0.31 vs 0.44,
respectively; P = .01).
• The top 3 pathogens were :
– MRSA (n = 70, 27.9%)
– Pseudomonas species (n = 40, 16.3%)
– Klebsiella species (n = 34, 13.3%).

Infect Control Hosp Epidemiol. 2013 Jul; 34(7): 657–662.

 Methicillin-Resistant
Staphylococcus aureus
(MRSA)
Epidemiology of MRSA
• Staphylococcus aureus commonly carried on skin or in
nose (25%-30%)1
• Healthcare-associated MRSA infections arise in the
hospital or healthcare setting,1-3 particularly among
elderly or sick patients1
• MRSA infections include skin infections, bone
infections, pneumonia, and bloodstream infections1
• MRSA is almost always spread by direct or indirect
physical contact with MRSA patients1

1. CDC. Available at: http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_clinicians.html#1.

2. Adapted from Tambyah PA, et al. Infect Control Hosp Epidemiol. 2003;24:436-8.
3. Campbell AL, et al. Infect Control Hosp Epidemiol. 2003;24:427-30.
MRSA Is a Growing Epidemic
Proportion of Staphylococcus aureus nosocomial infections resistant to oxacillin
(MRSA) among intensive care unit patients, 1995-2004.*

70
60
Resistance (%)

50
40
30
20
10
0
95

96

97

98

99

00

01

02

03

04
19

19

19

19

19

20

20

20

20

20
Year
*Source: NNIS System.

Adapted from CDC. Available at: http://www.cdc.gov/ncidod/dhqp/ar_mrsa_data.html.

 Global prevalence of MRSA
Worldwide prevalence of hospital-acquired MRSA

Unknown
<1%
1–5%
5–10%
10–25%
25–50%
>50%

• MRSA, methicillin-resistant Staphylococcus aureus.

Stefani S, et al. Int J Antimicrob Agents 2012;39:273–82.
Risk Factors Associated With MRSA
VAP

• Independent risk factors associated with MRSA pneumonia

– Intubation for more than 3 days (odds ratio [OR] 1.11;
confidence interval [CI] 1.03 to 1.18; P=0.001)
– Prior bronchoscopy (OR 5.8; CI 1.85 to 18.19; P=0.002)
• Prior therapy with multiple antibiotics showed a trend toward
statistical significance (OR 2.5; CI 0.87 to 7.7; P=0.08)
• Using a logistic regression analysis of 139 episodes of S
aureus pneumonia using MRSA as the dependent variable

Pujol M et al. Eur J Clin Microbiol Infect Dis. 1998;17:622-628.

Risk factors of MDR pathogens of HAP and VAP

July 2016
 Potential Sequelae of MRSA Infections

Mortality for MRSA versus MSSA5

• Increased risk of mortality1
• Increased morbidity2,3
• Prolonged hospitalization2,3
• Linked to increased cost1,2,4

0.1 0.5 1 5 10

1. Rubin RJ, et al. Emerg Infect Dis. 1999;5:9-17. Oddsratio

2. Carbon C. J Antimicrob Chemother. 1999;44(suppl A):31-6.
3. The Brooklyn Antibiotic Resistance Task Force. Infect Control Hosp Epidemiol. 2002;23:106-8.
4. Abramson MA, Sexton DJ. Infect Control Hosp Epidemiol. 1999;20:408-11.
5. Cosgrove SE, et al. Clin Infect Dis. 2003;36:53-9.
 Frequency of Occurrence of Bacterial Pathogens
Associated with CAP, HCAP, HAP, VAP – US (2002-2003)

S. aureus was a major pathogen of all pneumonias with higher rates in non-CAP
pneumonias.
Kollef MH, et al. Chest. 2005;128:3854-62.
 Microbiology of HAP & VAP
• Early onset HAP or VAP (occurs within the first 4
days after hospitalization or intubation) is most
often due to antibiotic-sensitive bacteria (e.g.,
oxacillin-sensitive Staphylococcus aureus,
Haemophilus influenzae, and Streptococcus
pneumoniae)
• Late-onset HAP or VAP is frequently caused by
antibiotic-resistant pathogens (e.g., oxacillin-
resistant Staph. aureus, Pseudomonas
aeruginosa, acinetobacter species, and
enterobacter species)

NEJM 340:627-634, 1999

Microbiology of HAP & VAP in Asia
 Defining appropriate therapy
● Inadequate therapy
– “. . .the microbiological documentation of infection…that was not
effectively treated at the time the causative microorganism and its
antibiotic susceptibility were known…”1

● Other factors to consider in defining appropriate therapy:1,2

– Microbiologic data (including lack of consistently predicting
outcome based on in vitro susceptibility)
– Monotherapy versus combination therapy
– Dose and dosing frequency
– Penetration
– Timing
– Toxicity
– Risk of influencing resistance
– Prior antibiotic use (Collateral Damage)

1. Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.

2. Kollef MH et al. Chest 1999;115:462-474.
Mortality* Associated with Initial Inadequate Therapy
in Critically Ill ICU Patients with HAP or Sepsis

16.2%
Alvarez-Lerma, 1996** 24.7% Initial adequate
38% therapy
Luna, 1997 91%
Initial inadequate
15.6%
Rello, 1997 37% therapy
33.3%
Kollef, 1998 60.8%

28.4%
Ibrahim, 2000*** 61.9%
24%
Harbarth, 2003*** 39%
31%
Valles, 2003*** 63%

Mortality
0% 20% 40% 60% 80% 100%
*Mortality refers to crude or infection-related mortality. **Includes patients with HAP.
***Patients had blood stream infections rather than pneumonia as in the other studies.
Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.
Luna CM et al. Chest 1997;111:676-685.
Rello J et al. Am J Respir Crit Care Med 1997;156:196-200. Kollef MH et al. Chest
1998;113:412-420.
Ibrahim EH at al. Chest 2000;118:146-155. Harbarth S et al. Am J Med 2003;115:529-
535. Valles J et al. Chest 2003;123:1615-1624.
2016 IDSA Guideline of adult HAP & VAP
Management

July 2016
Empirical Therapy in VAP and HAP

July 2016
Empirical Therapy in VAP and HAP

July 2016
Empirical Therapy in VAP and HAP

July 2016
Empiric therapy in HAP

July 2016
Empiric therapy in HAP with VAP

July 2016
 Guideline recommendation for MRSA
Pneumonia

IDSA Guideline MRSA 2011

Role of Linezolid in HAP treatment
• Some recommendation of Linezolid :
• Empiric treatment for MRSA HAP with VAP : strong
recommendation, moderate-quality evidence
• Empiric treatment for MRSA HAP without VAP : strong
recommendation, low-quality evidence\
• Pathogen specific therapy for MRSA HAP/VAP : strong
recommendation, moderate-quality evidence).
• The choice between vancomycin and linezolid maybe
guided by patient-specific factors such as blood cell counts,
concurrent prescriptions for serotonin-reuptake inhibitors,
renal function, and cost.

July 2016
 MRSA pneumonia : Vancomycin vs Linezolid?

•No difference in microbiologic success rates •Limitations of post-hoc analysis prevent

•No difference in eradication rates of MRSA drawing definitive conclusions
1Rubinstein CID 2001;32:402-12; 2Wunderink Clin Therap 2003;25:980-92; 3Wunderink Chest 2003;124:1789-1797
 Glycopeptides as Drugs of Choice for
Serious MRSA Infections
• Glycopeptides have been regarded as the drugs
of choice for serious MRSA infections, but their
use may be limited by:
– Potential toxicity1
– Need for parenteral administration1
– Emerging vancomycin resistance among S aureus
isolates (VRSA)2,3

• Need for alternative therapies for serious

staphylococcal infections4

1. Khare M, Keady D. Expert Opin Pharmacother. 2003;4:165-77.

2. Hiramatsu K. Lancet Infect Dis. 2001;1:147-55.
3. Pfeltz RF, et al. Curr Drug Targets Infect Disord. 2004;4:273-94.
4. Nathwani D, et al. Int J Antimicrob Agents. 2003;21:521-4.
 Linezolid in Pneumonia
• Linezolid is active against Gram-positive including resistant Gram-
positive organisms and shows in vitro activity with MIC90s of ≤4
g/mL1
– Methicillin-resistant and -susceptible strains of S aureus (MIC90 ≤4 µg/mL)1
– Methicillin-resistant and -susceptible strains of Staphylococcus epidermidis
(MIC90 = 2 µg/mL)2
– Vancomycin-resistant enterococci (MIC90 <2 µg/mL)1

• Linezolid provides excellent lung penetration1

• Linezolid 600 mg q12h has been shown in clinical trials to be an
effective treatment for nosocomial pneumonia caused by S aureus
(methicillin-susceptible and -resistant strains) or S pneumoniae
(penicillin-susceptible strains only)1

1 Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.

2 Zurenko GE et al. Antimicrob Agents Chemother. 1996;40:839-845.
Zyvox - Linezolid
• A synthetic oxazolidinone antibiotic, the first to undergo extensive clinical
evaluation
• Active against Gram-positive bacteria
• Available as i.v. and oral formulations
• Oral formulation has 100% bioavailability

• Indicated for MRSA & VRE of Infection caused Gram + :

– Nosocomial Pneumonia
– Complicated skin and soft tissue infection, including DFI, without concomitant osteomyelitis
Thank you