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MRSA

診斷、治療與醫院感染管制

主講人:李垣樟醫師
臺北醫學大學附設醫院
課程大綱

1.MRSA的簡介

2.MRSA的治療

3.MRSA的發病機制

4.MRSA的感染管制
1. MRSA簡介
Diversity in Staphylococcus aureus
Infections

資料來源:臺北醫學大學附設醫院成人感染科(left),
Lancet Infectious Diseases Vol 5. Issue 12. 751-762 (right)
Diversity in S. aureus Infections

資料來源:臺北醫學大學附設醫院成人感染科
Association Between the Staphylococcus aureus Bacteremia
(SAB) Score and the Probability of Complicated SAB

• 1 point : community-acquired infection, skin findings suggestive of acute systemic infection, and
persistent fever at 72 h.
• 2 points: a positive result of follow-up blood culture at 48-96 h.

資料來源:Corey G R Clin Infect Dis. 2009; 48: S254-S259


MRSA: Methicillin-Resistant
Staphylococcus aureus
• The mecA gene
– Central genetic
determinant of MRSA
– Encodes for PBP2A :
low affinity for β-lactam
antibiotics
– Staphylococcal
Cassette Chromosome
mec (SCC mec): foreign
DNA

資料來源:J. Clin. Invest. 114: 1693-1696 (2004)


MRSA: A Major Pathogen in Hospitals(1/2)

• Nosocomial blood stream infections


• Healthcare-associated pneumonia
• Surgical-site infections
• Infections in intensive care units and in critically
ill patients
MRSA: A Major Pathogen in Hospitals(2/2)

資料來源:Grundmann, H et al., Lancet 368 (2006) 874-885


Healthcare-associated MRSA
(HA-MRSA)
• One of the few pathogens routinely implicated in
nearly every type of hospital-acquired infection
• Probably related in part to the organism's
capacity for biofilm formation on invasive, foreign
devices such as endotracheal tubes and urinary
and endovascular catheters
Public Health Importance of MRSA
• Increase morbidity
– Multiple drug resistant
– Patient condition
• Prolonged hospital stay--17-21days
• Extra hospital costs--US$5,000
• Increased mortality
– MRSA infection: mortality risk 20-40%
– Excess Mortality Risk: 20%
(using uninfected patients as comparison group)
抗藥性金黃色葡萄球菌感染與非抗藥性金黃色葡
萄球菌感染住院天數與醫療費用之比較
MRSA non-MRSA
Length of stay P
infection infection
SICU (mean) 40.6 6.56 <0.001

Total hospital (mean) 75.4 23.3 <0.001

MRSA non-MRSA
Costs P
infection infection

SICU (mean) 763,982 198,387 <0.001*

Total hospital (mean) 954,476 255,164 <0.001*

* p<0.05

資料來源:臺北醫學大學附設醫院資料
2004至2013年第2季醫學中心及區域醫院加護
病房MRSA百分比

資料來源:CDC, Taiwan
MRSA Increasingly Recognized in Infections Among Persons
in the Community without Established Risk Factors for MRSA

資料來源:N Engl J Med 2006; 355: 666-74


SCCmec Structure and Epidemiology of
MRSA Clones

資料來源:Cell. Mol. Life Sci. (2010) 67: 3064


HA-MRSA vs. CA-MRSA (1/2)

資料來源:Expert Opin Pharmacother. 2010 Dec; 11 (18): 3009-25


HA-MRSA vs. CA-MRSA (2/2)

資料來源:臺北醫學大學附設醫院
The Toxin Panton-Valentine Leukocidin
(PVL) in CA-MRSA

CA-MRSA

資料來源:PNAS 2010; 107: 5587-5592


Epidemiology of CA-MRSA
• In cases of staphylococcal necrotizing CAP, 85%
were PVL positive, whereas none of HAP strains
were positive for the toxin.
• Patients with PVL-positive strains were
significantly more likely to have had an
antecedent influenza-like illness.
• PVL-positive patients were also younger and
less likely to survive their infection; overall
mortality was >40%.

資料來源:Seminars in Respiratory and Critical Care Medicine,


volume 26, number 6, 2005
A Case of Influenza B Co-infection
with CA-MRSA

資料來源:臺北醫學大學附設醫院成人感染科
Evolving Epidemiology
• The CA-MRSA and HA-MRSA classifications are
no longer distinct, since patients can develop
MRSA colonization in one realm and develop
manifestations of infection in another.
• Community-onset, HA-MRSA observed with
increasing frequency among patients in
community settings.
• Patients with MRSA infections due to
“community-associated” strains with increasing
frequency among patients in hospital settings.
2.MRSA 的治療
MRSA
• Methicillin resistance in S. aureus: an oxacillin
minimum inhibitory concentration (MIC) ≥4
• Cross resistant to other β-lactam agents
Vancomycin
• Antibiotic of choice for the treatment of invasive
methicillin-resistant S. aureus (MRSA) infections
• Alternative agents
– In the setting of adverse effects due to vancomycin or
infection with a pathogen with reduced susceptibility to
vancomycin coupled with a poor clinical response
• MIC creep
– Decrease in susceptibility of S. aureus isolates to
vancomycin
Vancomycin MIC Population Distribution
2001-2005

MIC creep

資料來源:Steinkraus G et al. J. Antimicrob. Chemother. 2007; 60: 788-794


Vancomycin
• Inferior to β-lactams for treatment of MSSA
bacteremia and infective endocarditis
• Tissue penetration
– Limited for bone, lung epithelial lining fluid and
cerebrospinal fluid
• MIC breakpoints
– S: MIC ≤2, I: MIC 4 to 8, R: MIC ≥16
• For the treatment of infection due MRSA isolates
with vancomycin MIC >1, optimal
pharmacodynamic targets may not be achievable
Vancomycin Dosing Guideline

資料來源:臺北醫學大學附設醫院藥劑部
Vancomycin 劑量建議表(1/2)

資料來源:臺北醫學大學附設醫院藥劑部
Vancomycin 劑量建議表(2/2)

資料來源:臺北醫學大學附設醫院藥劑部
Daptomycin (1/3)
• A cyclic lipopeptide bactericidal antibiotic that
causes depolarization of the bacterial cell
membrane
• Alternative to standard therapy in the treatment
of patients with S. aureus bacteremia and
osteoarticular infections
• Should not be used for treatment of MRSA
pneumonia since its activity is inhibited by
pulmonary surfactant

資料來源:UpToDate
Daptomycin (2/3)
• The daptomycin MIC may increase during
therapy and may be influenced by patient
exposure to vancomycin.

• Daptomycin susceptibility testing is critical both


prior to and during daptomycin therapy,
particularly if prolonged therapy and there is
microbiological evidence of persistent infection
during therapy.

資料來源:UpToDate
Daptomycin (3/3)
• Peripheral neuropathy and myopathy : serial
measurements of serum creatine kinase at least
weekly.
• Drug should be discontinued in patients with
symptomatic myopathy and CPK ≥5 times ULN
(upper limit of normal) or in asymptomatic
patients with CPK ≥10 times ULN.
• Eosinophilic pneumonia.

資料來源:UpToDate
Linzolid (1/2)
• A bacteriostatic, synthetic oxazolidinone
antibiotic that inhibits initiation of protein
synthesis at the 50S ribosome.
• Enhanced efficacy against strains producing
toxins such as Panton-Valentine leukocidin,
alpha-hemolysin, and toxic-shock syndrome
toxin-1.
• Excellent tissue distribution.

資料來源:UpToDate
Linzolid (2/2)
• Nosocomial pneumonia and complicated skin
and skin-structure infections.
• An outbreak of linezolid resistant S. aureus in an
intensive care setting.
• Adverse effects: thrombocytopenia, anemia,
lactic acidosis, peripheral neuropathy, serotonin
toxicity, and ocular toxicity.
• Serotonin syndrome: reversibly inhibit
monoamine oxidase.
資料來源:UpToDate
Tigecycline (1/2)
• Glycylcycline antibiotic derived from minocycline.

• Gram-positive pathogens (including MRSA,


VRE, and penicillin-resistant Streptococcus
pneumoniae), gram-negatives (important
exceptions include Pseudomonas and Proteus
species), anaerobes, and atypical species.

資料來源:UpToDate
Tigecycline (2/2)
• Complicated skin and skin-structure infections
and complicated intra-abdominal infections.

• Given concerns regarding achieving adequate


tigecycline serum drug concentrations, caution
should be used with tigecycline for the treatment
of patients with bacteremia.

資料來源:UpToDate
Teicoplanin
• Glycopeptide
• Same spectrum of activity and similar efficacy as
vancomycin.
• A longer half-life than vancomycin.
• Given intramuscularly, outpatient management.
• Significantly fewer episodes of red man
syndrome and other adverse events in patients
treated with teicoplanin.
• A lower risk of nephrotoxicity.

資料來源:UpToDate
Rifampicin
• A bactericidal agent that inhibits DNA dependent
RNA polymerase
• Should not be used as a single agent due to the
rapid emergence of resistance
• Rifampin used in combination with other anti-
staphylococcal agents in the treatment of
prosthetic device infections or bone infections
Fusidic Acid
• Inhibits protein synthesis by blocking aminoacyl-s
RNA transfer to protein.
• Emergence of resistance in monotherapy.
• Use of fusidic acid together with statins is
associated with risk of rhabdomyolysis.
Fluoroquinolones
• Should not be used to treat invasive MRSA
infections; resistance can emerge during
therapy.
Empirical Coverage of CA-MRSA in Outpatients with
Skin and Soft Tissue Infections

• Clindamycin

• Trimethoprim-sulfamethoxazole

• Tetracycline (minocycline or doxycycline)

• Linezolid

資料來源:Clinical Practice Guidelines. CID 2011: 52 (1February)


3. MRSA的發病機制

Pathogenesis of MRSA Infection


Pathogenesis of MRSA Infection

• Anterior nares: main ecological


niche for S.aureus
• Colonization increased risk of
subsequent infection
• Blood isolates were identical to
nasal isolates in 82% of patients
Conclusions: A substantial proportion of cases of S. aureus bacteremia appear to be
of endogenous origin since they originate from colonies in the nasal mucosa. These
results provide support for strategies to prevent systemic.
S. aureus infections by eliminating nasal carriage of S. aureus.

資料來源:N Engl J Med 2001: 344: 11-6


Colonization and Autoinfection
• Most S. aureus disease caused by the patient’s
own bacteria.
• Colonization with S. aureus raises the risk for
staphylococcal infection after invasive medical or
surgical procedures.
• Screening and subsequent treatment to
eliminate carriage before infection develops.
Antibiotic Use
• Antibiotic use (particularly cephalosporin and
fluoroquinolone use) correlates with the risk for
MRSA colonization and infection.
• Patients who had received cephalosporins for ≥5
days were three times more likely to acquire
MRSA than those who had not received
cephalosporins.
HIV Infection
• HIV-infected individuals are at increased risk for
MRSA colonization and infection.
• The primary sites of these infections were skin
and soft tissue (83 percent).
• Risk factors: advanced immunosuppression.
(CD4 count <50 high plasma HIV RNA)
(>100,000 and lack of antiretroviral therapy)
Hemodialysis
• Patients with long-term catheters for
hemodialysis access are at significantly higher
risk for invasive catheter-related infections due
to MRSA.
• The incidence of invasive MRSA infection was
100 times higher among dialysis patients than in
the general population (45 versus 0.4 per 1000
patients).
Complicated MRSA Bacteremia with
Hemodialysis
• 79 y/o male
• Uremia with regular
hemodialysis suffered
recurrent MRSA-
related perm-catheter
infection.

資料來源:臺北醫學大學附設醫院成人感染科
Long-Term Care Facilities
• S. aureus accounted for about 15 percent of
acquired infections.
• MRSA-colonized residents are frequently
transferred between
hospitals and long-term
care facilities.

資料來源:Elsevier 2004. Infectious Diseases 2e


MRSA in ICUs(1/2)

資料來源:臺北醫學大學附設醫院感染管制室
MRSA in ICUs(2/2)
• Adult ICUs, the average admission prevalence
of MRSA colonization is around 8% ( from about
5% to 20%).
• The risk of MRSA infection among MRSA-
colonized patients varies from 10% to 25%.
• 1 in 20 MRSA-free patients admitted to an ICU
will acquire MRSA colonization (incidence, 2% to
12% ).
• Per-day risk of MRSA acquisition range from
0.5% to 1%.
Staphylococcus aureus Colonization and the
Risk of Infection in Critically Ill Patients

資料來源:Infect Control Hosp Epidemiol 2005; 26: 622-628


Transmission
• Contact with contaminated wounds or dressings
of infected patients.
• Contact with another individual's colonized intact
skin.
• Contact with contaminated inanimate objects.
• Inhalation of aerosolized droplets from chronic
nasal carriers.
Patient and Environmental Sources of
MRSA

資料來源:Crit Care Med 2010; 38 [Suppl.]: S335-S344


Exogenous Transmission

Failure to clean hands results


in between-patient cross-transmission
資料來源:WHO
Endogenous Infection

資料來源:Elsevier 2004. Infectious Diseases 2e


Risk Factors for MRSA

資料來源:UpToDate
4. MRSA的感染管制
防止多重抗藥性菌種傳播的措施(1/2)
• Hand hygiene
• Standard and contact precautions (e.g., gowns,
gloves)
• Cohorting of patients and staff
• Evidence-based practices to prevent device-
related infections
• Environmental cleaning and disinfection
• Equipment cleaning and disinfection

資料來源:Crit Care Med 2010; 38 [Suppl.]: S345-S351


防止多重抗藥性菌種傳播的措施(2/2)
• Identification and isolation of colonized patients
• Risk factor identification
• Active surveillance cultures
• Surveillance of microbiology results
• Outbreak investigation
• Microbiological detection methods
• Antimicrobial stewardship

資料來源:Crit Care Med 2010; 38 [Suppl.]: S345-S351


Hand Hygiene
• Implementation of a hand-hygiene campaign led
to an increase in the rate of hand hygiene
compliance (48 to 66 percent) with a
concomitant decrease in the rate of MRSA
transmission (2.16 to 0.93 episodes per 1,000
patient-days) .

資料來源:臺北醫學大學附設醫院感染管制室
MRSA 接觸隔離

資料來源:臺北醫學大學附設醫院感染管制室
Caring for Patients with MRSA
• Private room: 2-3 P’t with MRSA.
• Clean, non-sterile gloves.
• Wear a gown and a mask (the most appropriate
setting for masks is
probably in the care of
patients with active
pulmonary infection due
to MRSA).
• Alcohol-based hand rub.

資料來源:臺北醫學大學附設醫院感染管制室
預防多重抗藥性菌種在病房傳播(1/2)
• 優先考慮將多重抗藥性菌種病患安置於單人病房
內,或鄰床暫不簽床。
• 其次將帶有相同多重抗藥性微生物的病患,集中
照護於指定的區域(例如:病房、隔間、病患照
護區)固定人員照護。
• 如果集中照護不可行,建議不要將帶多重抗藥性
微生物病患安置於高感染風險或預期長期住院病
人旁。(低感染風險病人是指:無免疫功能缺損,
未使用抗生素,沒有開放性傷口,沒有引流管,
沒有導尿管,沒有中心靜脈導管者)。
預防多重抗藥性菌種在病房傳播(2/2)
• 需採取接觸隔離措施:當可能涉及接觸病人或受
到汙染的病人環境時,應穿上隔離衣與戴上手套,
離開病室前應先脫除隔離衣與手套。
• 病人在單位間互轉,應先告知是否為多重抗藥性
菌種,以便床位調度(根據上述原則)。
• 他院轉入病人,應特別評估是否為多重抗藥性菌
種。
• 上述措施執行有疑問,請與單位負責感染控制人
員或單位負責感染科醫師聯繫討論。
組合式感染管制措施(Bundle Intervention)(1/2)

資料來源:臺北醫學大學附設醫院感染管制室
組合式感染管制措施(Bundle Intervention)(2/2)

資料來源:臺北醫學大學附設醫院感染管制室
Collateral Damage from Use of Antibiotics

資料來源:Paterson D L Clin Infect Dis. 2004; 38: S341-S345 68


Fluoroquinolone Use and Methicillin-resistant
Staphylococcus aureus Isolation Rates in Hospitalized
Patients: A Quasi Experimental Study

• Observed and expected rates of methicillin-


resistant Staphylococcus aureus (MRSA)
isolation before and after fluoroquinolone class.
• Restriction at Caen Hospital, France, 1997-2004.

資料來源:Clinical Infectious Diseases 2006; 42: 778-84


Active Surveillance Cultures
• Appear to be most useful in the setting of hospital
outbreaks and among patients at high risk for
MRSA infection, such as patients in ICUs,
immuno-compromised patients, long-term care
facility residents, and patients on hemodialysis.
Infected patients

Colonized patients

資料來源:UpToDate. Topic:Prevention and control of methicillin-resistant


Staphylococcus aureus in adults
Recommendations for MRSA Admission
Screening
• History of MRSA colonization
• In intensive care
• Hospitalized in the previous 12 months
• Extensive contact with health care system
(nursing home residents, patients receiving
dialysis or patients receiving outpatient infusion
therapy)
• Received antibiotic therapy in the last three
months
• Skin or soft tissue infection at admission
Active Surveillance Cultures
• Anterior nares are a frequent site of MRSA
carriage (positive in 73 to 93 percent of carriers)
• Rectum may be an important reservoir among
those with CA-MRSA
• Throat cultures
• Areas of skin breakdown
HA-MRSA的病房分佈

 60% of MRSA nosocomial infections occuring among


patients in ICU---Am J Infect Control 2004; 32(8):470-485

資料來源:臺北醫學大學附設醫院感染管制室
MRSA Active Surveillance Bundle

資料來源:N Engl J Med 2011; 364: 1419-30


Decolonization(消除菌落移生)
• MRSA nasal colonization appears to precede
infection.
• Asymptomatic nasal carriage is not always
identifiable in the setting of MRSA infections.
• Other potentially important roles in transmission
include impaired host defenses and contact with
skin and/or fomites.
• Decolonization does not appear to be consistently
effective for eliminating MRSA carriage.
• Emergence of resistance to agents used for
decolonization.
Chlorhexidine
• Binds the bacterial cell wall, altering osmotic
equilibrium.
• Whole-body washing with chlorhexidine can
reduce MRSA skin colonization, but eradication
has been achieved only in combination with
nasal mupirocin, with or without systemic
antibiotics.
Mupirocin
• For eradication of nasal colonization.
• Applied to anterior nares twice daily for five to
seven days) inhibits bacterial protein and RNA
synthesis.
• Minimal toxicity and no structural similarity with
existing systemic antibiotics.
• High-level mupirocin resistance, mupA.
Decolonization (Eradication) of MRSA
Carrier
• 2% Mupirocin ointment applied to anterior
nares, three times daily x 5 days.
• 4% Chlohexidine gluconate solution full-body
washing daily x 5 days.

資料來源:Journal of Hospital Infection 2006; 63: S1-S44


MRSA Decolonization in ICUs(1/2)

資料來源:N Engl J Med 2013; 368: 2255-2265


MRSA Decolonization in ICUs(2/2)

資料來源:N Engl J Med 2013; 368: 2255-2265


新入住加護病房病人MRSA處理流程

資料來源:臺北醫學大學附設醫院感染管制室
Active Surveillance Intervention對外科
加護病房MRSA感染之影響

資料來源:臺北醫學大學附設醫院感染管制室
課程結束