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Using MRSA nasal swab PCR to guide de-escalation of empiric MRSA therapy: Does Swabbing Nares Do Well, or Is There Nary a Use?

Sean Coco, Pharm.D. PGY-1 Pharmacy Resident

Department of Pharmacy, CHRISTUS Santa Rosa Westover Hills, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio

March 13th, 2020

Learning Objectives: 1. Describe the importance of de-escalation of methicillin-resistant Staphylococcus aureus

(MRSA) therapy2. Discuss and evaluate the primary literature assessing the use of MRSA nasal swab

culture and PCR in guiding treatment3. Formulate an evidence-based recommendation regarding the clinical utility of MRSA

nasal swab

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I. Staphylococcus aureusA. History

1. Initially discovered in 1880a) Identified by Sir Alexander Ogston from a surgical abscess 1

2. Penicillin discovered in 1928 by Alexander Fleminga) Penicillin resistant S. aureus / Methicillin-susceptible S. aureus (MSSA) appeared in

1942 2

3. Methicillin introduced in 1959 for the treatment of penicillinase-producingStaphylococcusa) MRSA appeared within the next two years 3

Figure 1: Timeline of Penicillin and S. aureus

B. Common colonizer in humans 4

1. Can normally be found on the skin2. Up to 30% of the human population is colonized with S. aureus

C. S. aureus is a primary cause of multiple infectious etiologies1. Commonly seen in complex disease states such as endocarditis 5

a) Accounts for 15-40% of all infectious endocarditis cases and for the majority ofcases in patients who inject drugs 5

b) S. aureus endocarditis is associated with an in-hospital mortality rate of 20-30% 5

2. Seen in patients with both hospital-acquired pneumonia (HAP) and ventilator-associatedpneumonia (VAP)a) S. aureus accounts for 20-40% of all HAP and VAP and is associated with an all-cause

mortality rate of 55.5%.6

b) Seen in patients with community-acquired pneumonia (CAP) who have risk factorsfor MRSA 7

(1) MRSA has been identified as a potential pathogen in 8.9% of all CAP cases.6

3. A common cause of skin and soft tissue infections (SSTIs)a) Common skin infections that involves S. aureus include cellulitis, abscesses, diabetic

foot infections, and necrotizing fasciitis 8

(1) Between 8-25% of all SSTIs are thought to be due to S. aureus. 9

D. Virulence of S. aureus1. There are five stages in the pathogenesis of S. aureus infections 10

a) Colonization, local infection, systemic dissemination, metastatic infection, toxinosis(1) Colonization of the skin is completely asymptomatic and is not a cause for

concern.(2) Local infection with S. aureus can be caused by a cut or break in the skin which

can lead S. aureus to begin invading the body through the dermis.

Initially discovered in 1880 and identified by Sir Alexander

Ogston from a surgical abscess

Penicillin discovered in 1928 by Alexander

Fleming

Penicillin resistant S. aureus/ Methicillin-susceptible S. aureus (MSSA) appeared in

1942

MRSA appears in 1951 after broad use

of methicillin

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(3) After entering the body and reaching the bloodstream, S. aureus can easily disseminate throughout the body due to it being easily able to “stick” in different places in the body.

(4) Describe the importance of de-escalation of MRSA therapy (5) Once spread throughout multiple areas of the body, S. aureus can more easily

potentiate its toxins in order to damage the host. 11 2. Several virulence factors also aid in the pathogenicity of S. aureus 12

a) Staphylocoagulase- proteins activate prothrombin which converts fibrinogen to fibrin, leading to blood clotting (1) This can lead to the creation of vegetation in bacterial endocarditis which is

aided by fibrin barriers that decrease S. aureus clearance by leukocytes b) Von Willebrand factor binding proteins exhibit non-proteolytic prothrombin

activator activity and leads to the creation of a prothrombin complex similar to staphylocoagulase which can lead to clotting

E. Antibiotic resistance 13 1. Resistance to penicillin is due to the blaZ gene which encodes for a beta-lactamase that

breaks down penicillin 2. Resistance to methicillin is due to a binding site change in the penicillin-binding protein

2A (PBP2A) caused by the mecA gene a) The mecA gene also confers resistance to almost all beta-lactam antibiotics

3. Penicillin resistance is observed in 80% of all S. aureus isolates a) Of the resistant strains, 60% are reported to be MRSA, and 40% are stated to be

MSSA

b) However, MRSA rates have started to drop in recent years. 14

(1) Studies have shown MRSA having a decrease in resistance to antimicrobial agents from on average 4.5 antibiotics in 2000 to 3.7 antibiotics in 2014. 15

F. MRSA risk factors a) Prior hospitalization within 12 months, history of MRSA infection, infection within

the last three months, intravenous drug use, history of Vancomycin-resistant Enterococci (VRE), antibiotic use within the last 90 days, diabetes, and chronic renal failure 16

G. Treatment overview 1. Penicillin-susceptible S. aureus (PSSA) 17

a) Anti-staphylococcal penicillins are the drugs of choice (1) Higher 30-day mortality with cephalosporins treatment compared to anti-

staphylococcal penicillins (39% vs 10%) (P=0.004) 2. MSSA

a) Anti-staphylococcal penicillins (i.e. oxacillin and nafcillin) (1) Preferred first-line agents in several guidelines due to large amounts of data

supporting their efficacy 18, 19 b) Cephalosporins (i.e. cefazolin)

(1) Newer data have shown similar efficacy when compared to oxacillin/nafcillin for treatment of MSSA infections. Treatment failure rates of 15% for nafcillin vs 15% for cefazolin have been observed when treating MSSA bacteremia 20

3. MRSA a) Primarily treated with Vancomycin

(1) While other treatments exist, vancomycin is seen as the standard of treatment for MRSA

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(2) Treatment affected by toxicities and monitoring requirements (a) Current guidelines suggest a trough goal of 15-20 mcg/mL for vancomycin in

the setting of severe infections such as pneumonia, bacteremia, or endocarditis. 21

(b) Current guidelines suggest a trough goal of 10-15 mcg/mL for S. aureus cellulitis, SSTI, and UTI 21

(c) Nephrotoxicity may affect up to 43% of all patients taking vancomycin depending on the length of treatment. 22

b) Some alternatives to vancomycin include daptomycin and linezolid (1) Daptomycin

(a) Not appropriate for treatment of pneumonia due to deactivation by pulmonary surfactant.

(b) Increases creatinine phosphokinase levels and may lead to rhabdomyolysis 23

(2) Linezolid (a) Comes as an oral agent, which may facilitate outpatient treatment (b) Increases the risk of myelosuppression and serotonin syndrome 24

II. Importance of appropriate de-escalation of antibiotics

A. Mortality 1. Studies have shown that treating MSSA with anti-staphylococcal penicillins had a

significantly lower risk of mortality (7%) when compared to using vancomycin (20%) (95% CI 0.01, 0.76) 25

B. Resistance 1. Unnecessary use of anti-MRSA therapy increases resistance in S. aureus

a) Vancomycin-intermediate S. aureus (VISA) has been shown to possibly be linked to previous vancomycin use

(1) 54% of patients who have been diagnosed with VISA have been treated with vancomycin within the previous month. 26

2. Use of narrow therapy decreases resistance rates

a) The implementation of an electronic program for infectious disease (ID) consulting service in Melbourne, Australia led to a decrease in the use of broad-spectrum antibiotics. This in turn translated into a 10% decrease in the rates of MRSA 27

C. Toxicities

1. Use of MRSA agents can put patients at a high risk for toxicities

Table 1: Common MRSA drugs and adverse effects 28

Vancomycin Nephrotoxicity, ototoxicity, extravasation, severe skin reactions (Red Man’s syndrome, directly related to infusion rate)

Daptomycin Increased CPK levels, myopathy, rhabdomyolysis, peripheral neuropathy, eosinophilic pneumonia

Linezolid Myelosuppression, increased liver function tests’, serotonin syndrome (when used within 2 weeks of mono amine oxidase inhibitors)

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III. Diagnostic tools for MRSA A. Diagnostic tests

1. Culture-based testing a) Used to detect microbial growth in the blood, urine, tracheal aspirate, fluid

collections, wound, or other miscellaneous sources (1) On average, S. aureus begins to grow after about 24-48 hours in blood cultures

29 2. Molecular detection 30

a) Platforms such as Verigene or Biofire extract nucleic acid can check for specific bacteria and resistance markers through polymerase chain reaction (PCR) (1) These tests are quick and can return results in less than 2 ½ hours, but will only

test for the bacteria that are selected on the panel (a) If a panel for gram-positive bacteria is checked but a gram-negative bacteria

is growing, the panel will show fully negative B. Considerations for diagnostic tests

1. See appendix A for definitions of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

2. Culture-based testing a) Blood cultures can be contaminated by bacteria that are not truly causing an

infection (1) The likelihood that a blood culture growth is a contaminant depends on the type

of bacteria that grows (a) Bacteria such as S. aureus have a very low likelihood of being a contaminant

(1%), compared to coagulase-negative Staphylococcus has a high likelihood of being a contaminant (82%)31

b) Cultures may also not be accurate if the patient received antibiotics prior to a culture being obtained (1) Using antibiotics prior to obtaining cultures has shown to decrease positive

blood cultures in CAP patients by half (5.2% vs 2.6%) 32 3. Rapid diagnostic tests

a) Molecular detection (1) Specific sensitivities and specificities differ between molecules that are being

tested 33 (a) Gilman et al. 2015 showed Verigene had a sensitivity and specificity for

Staphylococcus species of 100% (2) Rapid diagnostic testing in suspected MRSA patients being tested for the mecA

gene has shown sensitivity of 93.9% and specificity of 98.6%. 34

(a) Since this test has a higher specificity, a negative result would likely be truly negative

(b) However, mecA is not only found in S. aureus. It is also found in Staph epidermidis which is a common contaminant. 35

IV. MRSA nare tests A. Initially, MRSA nares tests were done to help decrease the spread of MRSA by placing

patients with positive MRSA nares on contact precautions and treating patients with mupirocin36

B. A test where the nasal cavity is cultured to determine if MRSA is present within the nares 1. Is either tested using culture-derived means or through PCR 37

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a) MRSA nasal swabs have shown to have different sensitivities and specificities depending on if they are grown in a culture or PCR

Table 2: Differences between MRSA Nasal PCR and MRSA Nasal Culture

Type of nares test PCR Culture

Sensitivity 89-100% 62-91%

Time to growth 2 hours 24-48 hours

C. Use in current practice

1. The 2014 IDSA skin and soft tissue infections guidelines reference using MRSA nasal colonization as a risk factor warranting the use of vancomycin in patients with cellulitis, erysipelas, or surgical site infections 38

2. Previous HAP and VAP IDSA guidelines mention positive MRSA nares increase the risk of MRSA being cultured from respiratory samples but not enough data was available to make a recommendation 19 a) The guidelines do reference a study showing that using MRSA nares in critically ill

patients had poor specificity, sensitivity, PPV, and NPV. 39 3. The 2019 IDSA CAP guidelines do have an update for the use of MRSA nasal swabs

stating that MRSA nasal swabs can be used to withhold MRSA therapy when swabs are negative 7 a) The guidelines state that positive MRSA nasal swabs are not indicative of

pneumonia due to MRSA D. Previous studies from the mid to late 2000’s and the early 2010's had conflicting evidence

on when to use MRSA nares to guide therapy. Some studies showed high NPV for pneumonias, but there was not enough data to make a strong stance on using MRSA nares as a diagnostic tool 40

E. While prior studies showed the clinical utility of MRSA nasal swabs for de-escalation of therapy in patients with pneumonia, new data suggest that using MRSA nasal swabs could help with de-escalation of antibiotics in treatment of other infections as well

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Clinical Question: Can negative MRSA nasal swab be used to de-escalate empiric MRSA therapy?

Table 3: Robicsek A, Suseno M, Beaumont JL et al. Prediction of Methicillin-Resistant Staphylococcus aureus Involvement in Disease Sites by Concomitant Nasal Sampling. Journal of Clin Microbiology. 2007;46(2):588-592. 40

Objectives

• Determine if MRSA nares tests could be used to rule out MRSA infections

• Determine if MRSA nares could be used to rule in MRSA infections

• Determine if MRSA nasal-colonization could be used as a marker of antibiotic resistance

Methods

Retrospective, cohort study conducted between August 1, 2005 - January 31, 2007 at the Evanston Northwestern Healthcare system in Chicago, Illinois

Patient population

Inclusion Criteria: ● Patients who had a clinical culture

positive for any pathogen

Exclusion Criteria: ● Viral cultures ● Surveillance clinical cultures that were

unlikely to represent sites where MRSA disease is a significant consideration (ex. stool cultures, vaginal cultures)

Intervention

● MRSA nares were collected using BD-GeneOhm real-time PCR test, and the results were compared to cultures collected

● Only the first positive clinical culture in a 30-day period was used for each patient ● True MRSA infections were defined as:

○ Bloodstream infection - requires a positive blood culture ○ Respiratory tract infection - requires a positive respiratory culture, positive chest X-

ray, and a decision to treat ○ Urinary tract infection - requires a positive urine culture + decision to treat OR

>100,000 CFU/mL + at least 50 leukocytes per high power field ○ All other sites required a positive culture and a decision to treat

▪ Other sites in this study were most frequently taken from the abdominal wall, buttock, or breast.

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Baseline Characteristics

Table 3a: Prevalence of culture sites

Culture Site Number of cultures taken (% total)

Bloodstream 1012 (17.5%)

Respiratory 426 (7.3%)

Extremity 457 (7.9%)

Ulcer 72 (1.2%)

Urine 2948 (51.0%)

Other 864 (14.9%)

Total 5779 (100%)

Results

● n= 5779

Table 3b: Sensitivity, Specificity, and PPV for MRSA nares

Diagnostic characteristic Result of analysis to predict MRSA positive culture (95% CI)

Sensitivity 67% (62% - 72%) (95% CI)

Specificity 90% (89% - 90%) (95% CI)

PPV 27% (24% - 31%) (95% CI)

● MRSA nares screens were positive for 13.7% of the population ● MRSA was positive in 5.5% of all clinical cultures

Table 3c: Predictive values for MRSA nares PCR based on culture site

MRSA culture site

Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI)

Bloodstream 0.74 (0.59, 0.85) 0.88 (0.86, 0.90) 0.21 (0.15, 0.29) 0.99 (0.98, 0.99)

Respiratory 0.75 (0.55, 0.88) 0.90 (0.86, 0.92) 0.30 (0.20, 0.43) 0.98 (0.97, 0.99)

Extremity 0.61 (0.52, 0.70) 0.94 (0.92, 0.96) 0.76 (0.65, 0.84) 0.90 (0.86, 0.92)

Ulcer 0.70 (0.48, 0.86) 0.89 (0.77, 0.95) 0.70 (0.48, 0.86) 0.89 (0.77, 0.95)

Urine 0.77 (0.65, 0.86) 0.87 (0.86, 0.89) 0.11 (0.09, 0.15) 0.99 (0.99, 1.00)

Other 0.60 (0.49, 0.70) 0.96 (0.95, 0.97) 0.61 (0.49, 0.71) 0.96 (0.95, 0.97)

Total 0.67 (0.62, 0.72) 0.90 (0.89, 0.90) 0.27 (0.24, 0.31) 0.98 (0.97, 0.98)

● The NPV for half of the obtained cultures was high, with urine, bloodstream, and respiratory

cultures having an NPV of > 98% ● However, the NPV for cultures obtained from extremities or from ulcers were low (NPV ≤

90%) ● Cultures for “Other” had an NPV of about 96%. However, due to the lack of more specific data

as to where these cultures originate from, conclusions cannot be drawn from these results.

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Authors’ conclusions

The absence of nasal MRSA colonization was useful for ruling out MRSA involvement only if the prevalence of MRSA as a pathogen in the type of infection being assessed was low (e.g., < 10%).

Reviewer’s Critique

Strengths ● Large sample size ● Study has in-depth analysis of the

relationship between MRSA nares and clinical cultures

● Study used only nasal PCR

Limitations ● Study did not clarify exact numbers or

types of cultures obtained from the “other” category

● Relatively small portion of positive cultures were MRSA (5.5% of positive cultures were MRSA)

● Only the first positive culture in a 30-day period was used for each patient (a urine culture that was positive for E. coli may have overridden a possible MRSA infection in the blood).

● Study did not provide baseline characteristics of patients included in this study

Take-home points

● While an older study, this study did show a possible high NPV for MRSA nares regarding MRSA clinical cultures.

● Negative MRSA nares may be used to rule out MRSA infections ● Positive MRSA nares should not be used to rule in MRSA infections

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Table 4: Rioux J, Edwards J, Bresee L, et al. Nasal-Swab Results for Methicillin-Resistant Staphylococcus aureus and Associated Infections. The Canadian Journal of Hospital Pharmacy. 2017;70(2) 107-112 41

Objective

Describe the diagnostic characteristics of nasal-swab screening in predicting MRSA infections in hospitalized patients receiving empiric treatment with IV vancomycin

Methods

Retrospective, observational chart review between January and October 2015 for patients of the Peter Lougheed Centre in Calgary, Alberta

Patient population

Inclusion Criteria: ● Age > 18 years old ● Initiated on empiric IV vancomycin (first

dose within 48 hours) ● Documented nasal swab and culture

within 48 hours of admission ● Culture from either blood, sputum,

wound, bronchoalveolar lavage (BAL), or endotracheal (ET) tube within 48 hours of admission

Exclusion Criteria: ● Patients with cultures collected after

receiving the first dose of vancomycin ● Patients on long-term dialysis therapy

(due to higher risk of non-MRSA infections requiring vancomycin therapy such as coagulase-negative Staphylococcus line infections)

● The patient was previously included in the trial

Baseline Characteristics

Table 4a: Baseline Characteristics

● Total of 334 cultures included in the study; 60 patients had 2 or more culture sites

Characteristic No. (%) of Patients

Total number of Patients 273

Sex, male 176 (64.5)

Age (years) (mean ± SD) 55.8 ± 17.7

History of recent admission 73 (26.7)

Admitting service

Internal Medicine 146 (53.5)

Hospitalist 69 (25.3)

Intensive care 27 (9.9)

Cultures 334

Blood Culture 266 (79.6)

Wound Culture 36 (10.8)

ET aspirate 22 (6.6)

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Results

Table 4b: Sensitivity, Specificity, and PPV for MRSA nares

Diagnostic characteristic Result of analysis to predict MRSA positive culture (95% CI)

Sensitivity 58.3% (28.6% - 83.5%)

Specificity 93.9% (90.0% - 96.3%)

PPV 30.4% (14.1% - 53.0%)

● MRSA nares screens were positive for 8.4% of all nasal cultures ● 4.4% of all patients had a positive MRSA clinical culture

Table 4c: Negative predictive value of MRSA nares in newly admitted patients treated with empiric vancomycin

Subgroup NPV% (95% CI)

All cultures 98.0 (95.1 - 99.3)

Recently admitted 98.4 (90.5 - 99.9)

Not recently admitted 97.8 (94.2 - 99.3)

Blood culture 99.2 (96.7 - 99.9)

Non-blood culture 87.5 (70.1 - 95.9)

Authors’ conclusions

The high NPV of MRSA nasal-swab screening in a low prevalence settings suggest that a negative result on MRSA nasal-swab screening significantly reduces the probability of MRSA infection.

Reviewer’s Critique

Strengths ● Study had a large portion of patients with

blood cultures, which makes this easily generalizable for bacteremia

● This study gives solid data regarding the NPV value of MRSA nasal swabs in comparison to both blood culture and non-blood culture results

Limitations ● MRSA nares were done with cultures and

not PCR ● Small sample size ● Excluding dialysis patients does decrease

the generalizability of this trial when discussing dialysis patients who are at a higher risk of MRSA infections

● Significantly less cultures from non-blood sources, makes it difficult to generalize to other cultures

Take-home points

● MRSA therapy may be de-escalated when treating bloodstream infections in the presence of a negative MRSA nares culture.

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Table 5: Mergenhagen KA, Starr KE, Wattengel BA et al. Determining the utility of methicillin-resistant Staphylococcus aureus nares screening in antimicrobial stewardship. Clin Infec Dis. 2019 42

Objective

Determine the NPV of MRSA screening in the determination of subsequent positive clinical cultures for MRSA

Methods

Retrospective, cohort study between January 2007 and January 2018, across VA medical centers

Patient population

Inclusion Criteria: ● Age > 18 years old ● MRSA nares tested upon admission or

transfer to a VA inpatient facility

Exclusion Criteria:

• Discharged nares results

• Rectal swabs for VRE

• Autopsy results

• Cultures with disparate results (blood culture labeled as abscess) or where the collection type was missing

Intervention

● Positive and negative cultures were identified and classified into their culture source (e.g. blood, urine, wound), and then categorized to their most closely identified subcategory (e.g. urine catheter, sterile respiratory, peripheral blood)

● Positive MRSA cultures were defined as cultures taken after but within 7 days of MRSA nasal swab, that contained MRSA

● Negative MRSA cultures were defined as cultures taken after but within 7 days of MRSA nasal swab, that did not contain MRSA

Baseline characteristics

Table 5a: Baseline Characteristics

Characteristic No. of Patients

Number of clinical cultures taken 561,325

Number of unique patients 245,833

MRSA nares with PCR performed (%) 73.7

MRSA nares with standard culture (%) 26.3

Sex (male) 96.3%

Age (years) (mean ± SD) 68.2 ± 12.3

Cultures (most frequent)

Urine (%) 40

Wound (%) 24.7

Respiratory (%) 16.2

Blood (%) 12.5

MRSA incidence (%) 8.3

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Results

Table 5b: Sensitivity, Specificity, and PPV for MRSA nares including best and worst % by site

Characteristic Result of analysis to predict

MRSA positive culture (95% CI) Culture with highest

value (%) Culture with lowest

value (%)

Sensitivity 67.4% (67.0% - 67.9%) Peripherally Inserted central catheter lines

(79.1) Graft cultures (51.3)

Specificity 81.2% (81.1% - 81.3%) Heart tissue cultures

(93.7) Eye tissue cultures

(74.4)

PPV 24.6% (24.4% - 24.8%) Device cultures (56.3) Urine cultures (7.6)

• MRSA nares screens were positive for 22.9% of the cohort

Table 5c: Negative Predictive values for MRSA Nasal PCR + Nasal Culture

Current location NPV % (95% CI)

All cultures 96.5% (96.4% - 96.52%)

All blood 96.5% (96.3% - 96.6%)

Respiratory tract 96.1% (95.9% - 96.2%)

Sterile Respiratory 96.1% (95.9% - 96.4%)

Urine Catheter 99% (98.9% - 99.1%)

Wound (unspecified) 93.1% (93% - 93.3%)

Wound (sterile) 93.5% (93.3% - 93.6%)

• Majority of cultures had relatively high NPV for MRSA of above 96% with the exception of wound cultures which had an NPV of less than 94% (Ex. Sterile wound of upper/lower extremity + foot 89% NPV, skin graft 89.6% NPV)

Table 5d: Negative Predictive values PCR vs. Nasal Culture

Type Number- PCR NPV - PCR (95% CI)

Number Culture NPV- Culture

(95% CI)

Whole cohort 413,664 96.9%

(96.8% - 96.9%) 147,661

95.5% (95.4% - 95.6%)

Blood 51,928 96.8%

(96.7% - 97.0%) 18,257

95.4% (95.2% - 95.7%)

Respiratory Tract 66,242 96.6%

(96.5% - 96.8%) 24,670

94.6% (94.3% - 94.9%

Renal System 145,777 99.3%

(99.3% - 99.3%) 55,666

99.1% (99.0% - 99.2%)

Wound 101,423 93.9%

93.7% - 94.0%) 34,655

91.1% 90.9% - 91.4%)

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Figure 5e: Heat Map of NPV by state

• Heat map showing negative predictive values of MRSA nares screening in the United States

Authors’ conclusions

This study suggests that a negative MRSA nares swab taken within 7 days of culture is useful for predicting the absence of MRSA in a subsequent clinical culture. It is not, however, appropriate to use MRSA nares as a tool to predict current MRSA infection. Use of MRSA nares screening may improve patient care by avoiding potential toxicities associated with the use of unnecessary or broad antibiotics.

Reviewer’s Critique

Strengths ● Very large trial ● Provided data on a state as well as on a

national level ● Was done mostly with PCR ● Gave data regarding using MRSA nares

with PCR vs. culture ● Broke down to useful subcategories

Limitations ● The study did not confound for positive

cultures that may not have been true cultures

● Almost the entire population was male (96.3%)

● Large percentage of the positive cultures was from urinary sources, which is not a common source of MRSA

● No baseline characteristics other than ages and sex.

Take-home points

● Using MRSA nares as a negative predictive marker is appropriate depending on the likely source of infection

○ It would be appropriate for patients with pneumonia, bloodstream infections, or UTIs.

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● Using MRSA nares to confirm the use of MRSA therapy is inappropriate ● Use of PCR for MRSA nares appears to have a slightly higher NPV compared to culture-based

diagnostic tests.

V. Literature summary

Table 6: Literature Summary

Robicsek, et. al 200739 Rioux, et. al 201740 Mergenhagen, et. al 201941

Use of MRSA nares as a negative predictive marker

may be appropriate; however, using it as a positive

marker does not seem appropriate

Using MRSA nares as a negative predictive marker

may be appropriate for bloodstream infections

Use of MRSA nares as a negative predictive marker

seems appropriate for suspected urine, blood, and

respiratory infections

VI. Recommendations

A. The use of MRSA nares PCR testing as an antimicrobial stewardship tool to guide de-escalation of therapy in certain clinical situations may be appropriate 1. Current data only supports de-escalation of therapy if MRSA prevalence is less than 10%

at the institution B. Due to the lack of baseline characteristics regarding patients with risk factors (ex. dialysis, IV

drug use), clinical judgement should be used in combination with results to guide treatment C. While use of MRSA nasal cultures will take longer than MRSA nasal PCR to be finalized as

negative, a negative MRSA nasal swab from a culture can still be used as a negative predictive marker.

D. MRSA nares should not be used to guide treatment in patients with skin and soft tissue infections, wound infections, or VAP

Table 7: Summary of recommendations for using MRSA nares as a negative predictive tool

Site of infection Should negative MRSA nares be used to de-escalate therapy

Bloodstream Yes

Respiratory tract Yes*

Urinary Tract Yes**

Wound No

Ulcer No

Skin No

* Due to prior evidence of low NPV in patients with VAP, MRSA nares should not be used to guide therapy. **Empiric therapy with vancomycin may be appropriate should the patient have a history of gram positive UTI even if MRSA nares are negative

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References:

1. Khan MF. Brief History of Staphylococcus aureus: A Focus to Antibiotic Resistance. EC

Microbiology 2017;5(2):36-39.

2. Rammelkamp CH, Maxon T. Proc. Resistance of Staphylococcus aureus to the Action of

Penicillin. Royal Soc. Exper. Biol. Med. 1942;51:386–389. doi:10.3181/00379727-51-13986.

3. Jevons MP. “Celbenin” - resistant Staphylococci. Br Med J I, 124-125, 1961.

4. Adele Sakr, Bregeon F, Mege JL, et al. Staphylococcus aureus Nasal Colonization: An Update on

Mechanisms, Epidemiology, Risk Factors, and Subsequent Infections. Front Microbiol. 2018; 9:

2419. doi:10.3389/fmicb.2018.02419.

5. Asgeirsson H, Thalme A, Weiland O. Staphylococcus aureus bacteraemia and endocarditis -

epidemiology and outcome: a review. Dis (Lond). 2018 Mar;50(3):175-192.

doi:10.1080/23744235.2017.1392039.

6. Rubistein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus

aureus. Clin Infect Dis. 2008 Jun 1;46 Suppl 5:S378-85. doi:10.1086/533594.

7. Metlay Jp, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-

acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and

Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67.

doi: 10.1164/rccm.201908-1581ST.

8. Ray GT, Suaya JA, Bacter R. Incidence, microbiology, and patient characteristics of skin and soft-

tissue infections in a U.S. population: a retrospective population-based study. BMC Infect Dis.

2013 May 30;13:252. doi:10.1186/1471-2334-13-252.

9. Cranendonk DR, Lavrijsen APM, Pins JM, et al. Cellulitis: current insights into pathophysiology

and clinical management. Neth J Med. 2017 Nov;75(9):366-378.

10. Archer GL. Staphylococcus aureus: a well-armed pathogen. Clin Infect Dis. 1998 May;26(5):1179-

81. doi:10.1086/520289.

11. Katie Maurer, Reyes T, Alonzo F, et al. Autophagy Mediates Tolerance to Staphylococcus aureus

Alpha-Toxin. Cell Host Microbe. 2015 Apr 8; 17(4): 429–440. doi:10.1016/j.chom.2015.03.001.

12. P. Panizzi, Friedrich R, Fuentes P, et al. The staphylocoagulase family of zymogen activator and

adhesion proteins. Cell Mol Life Sci. 2004 Nov; 61(22): 2793–2798. doi:10.1007/s00018-004-

4285-7.

13. Lowy FD, Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest. 2003

May;111(9):1265-73. doi:10.1172/JCI200318535.

14. Styers D, Sheehan DJ, Hogan P, et al. Laboratory-based surveillance of current antimicrobial

resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States.

Ann Clin Microbiol Antimicrob. 2006 Feb 9;5:2. doi:10.1186/1476-0711-5-2.

15. Sanjat K, Abdul MR, Thayer M, et al. Trends in Antibiotic Susceptibility in Staphylococcus aureus

in Boston, Massachusetts, from 2000 to 2014. J Clin Microbiol. 2018 Jan; 56(1): e01160-17.

doi:10.1128/JCM.01160-17.

16. Teshome BF, Lee GC, Reveles KR, et al. Application of a methicillin-resistant Staphylococcus

aureus risk score for community-onset pneumonia patients and outcomes with initial treatment.

BMC Infect Dis. 2015; 15: 380. doi:10.1186/s12879-015-1119-1.

Coco 17

17. Nissen JL, Skov R, Knudsen, et al. Effectiveness of penicillin, dicloxacillin and cefuroxime for

penicillin-susceptible Staphylococcus aureus bacteraemia: a retrospective, propensity-score-

adjusted case-control and cohort analysis. J Antimicrob Chemother. 2013 Aug;68(8):1894-900.

doi:10.1093/jac/dkt108.

18. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis,

Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare

Professionals From the American Heart Association. Circulation. 2015 Oct 13;132(15):1435-86.

doi:10.1161/CIR.0000000000000296.

19. Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and

Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases

Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-

e111. doi:10.1093/cid/ciw353.

20. Shinwon L, Pyoeng CG, Kyoung-Ho S, et al. Is Cefazolin Inferior to Nafcillin for Treatment of

Methicillin-Susceptible Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother. 2011

Nov; 55(11): 5122–5126. doi:10.1128/AAC.00485-11.

21. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of

consensus recommendations from the infectious diseases Society of America, the American

Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin

Infect Dis. 2009 Aug 1;49(3):325-7. doi:10.1086/600877.

22. Jeffres MN, Isakow W, Doherty JA, et al. A retrospective analysis of possible renal toxicity

associated with vancomycin in patients with health care-associated methicillin-resistant

Staphylococcus aureus pneumonia. Clin Ther. 2007 Jun;29(6):1107-15.

doi:10.1016/j.clinthera.2007.06.014.

23. Metwali H, Elder K. Dose-independent daptomycin associated rhabdomyolysis: Case report. J

Basic Clin Pharma October-2018;9(3): 286-288.

24. Hachem RY, Hicks K, Huen A, et al. Myelosuppression and serotonin syndrome associated with

concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow

transplant recipients. Clin Infect Dis. 2003 Jul 1;37(1):e8-11. doi:10.1086/375689.

25. Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin

versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia. BMC Infect Dis.

2011 Oct 19;11:279. doi:10.1186/1471-2334-11-279.

26. Park J.W., Lee H, Kim J.W., et al. Characterization of Infections with Vancomycin-Intermediate

Staphylococcus aureus (VISA) and Staphylococcus aureus with Reduced Vancomycin

Susceptibility in South Korea. Sci Rep 9, 6236 (2019). https://doi.org/10.1038/s41598-019-

42307-6.

27. Buising KL, Thursky KA, Robertson BM, et al. Electronic antibiotic stewardship--reduced

consumption of broad-spectrum antibiotics using a computerized antimicrobial approval system

in a hospital setting. J Antimicrob Chemother. 2008 Sep;62(3):608-16. doi:10.1093/jac/dkn218

28. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at:

http://online.lexi.com. Accessed 12/23/19.

Coco 18

29. Ning Y, Hu R, Yao G, et al. Time to positivity of blood culture and its prognostic value in

bloodstream infection. Eur J Clin Microbiol Infect Dis. 2016 Apr;35(4):619-24.

doi:10.1007/s10096-016-2580-5.

30. Coleman WB, Tsongalis G. Diagnostic Molecular Pathology: a Guide to Applied Molecular

Testing. Amersterdam: Elsevier/AP, Academic Press is an imprint of Elsevier; 2017.

31. Pien BC, Sundaram P, Raoof N, et al. The clinical and prognostic importance of positive blood

cultures in adults. Am J Med. 2010 Sep;123(9):819-28. doi:10.1016/j.amjmed.2010.03.021.

32. Harris AM, Bramley AM, Jain S, et al. Influence of Antibiotics on the Detection of Bacteria by

Culture-Based and Culture-Independent Diagnostic Tests in Patients Hospitalized With

Community-Acquired Pneumonia. Open Forum Infect Dis. 2017 Feb 10;4(1):ofx014.

doi:10.1093/ofid/ofx014.

33. Siu GK, Chen JH, Lee RA, et al. Performance Evaluation of the Verigene Gram-Positive and Gram-

Negative Blood Culture Test for Direct Identification of Bacteria and Their Resistance

Determinants from Positive Blood Cultures in Hong Kong. PLoS One. 2015 Oct

2;10(10):e0139728. doi:10.1371/journal.pone.0139728.

34. Kaplan S, Marlowe EM, Hogan JJ, et al. Sensitivity and Specificity of a Rapid rRNA Gene Probe

Assay for Simultaneous Identification of Staphylococcus aureus and Detection of mecA. J Clin

Microbiol. 2005 Jul; 43(7): 3438–3442. doi:10.1128/JCM.43.7.3438-3442.2005.

35. Shahin Najar-Peerayeh, Moghadas AJ, Behmanesh M. Antibiotic Susceptibility and mecA

Frequency in Staphylococcus epidermidis, Isolated From Intensive Care Unit Patients.

Jundishapur J Microbiol. 2014 Aug; 7(8): e11188. doi:10.5812/jjm.11188.

36. Hill RL, Duckworth GJ, Caswell MW. Elimination of nasal carriage of methicillin-resistant

Staphylococcus aureus with mupirocin during a hospital outbreak. J Antimicrob

Chemother. 1988 Sep;22(3):377-84. doi:10.1093/jac/22.3.377.

37. Paule SM, Mehta M, Hacek DM, et al. Chromogenic media vs real-time PCR for nasal surveillance

of methicillin-resistant Staphylococcus aureus: impact on detection of MRSA-positive persons.

Am J Clin Pathol. 2009 Apr;131(4):532-9. doi:10.1309/AJCP18ONZUTDUGAQ.

38. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management

of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin

Infect Dis. 2014 Jul 15;59(2):e10-52. doi:10.1093/cid/ciu444.

39. Sarikonda KV, Micek ST, Doherty JA, et al. Methicillin-resistant Staphylococcus aureus nasal

colonization is a poor predictor of intensive care unit-acquired methicillin-resistant

Staphylococcus aureus infections requiring antibiotic treatment. Crit Care Med. 2010

Oct;38(10):1991-5. doi:10.1097/CCM.0b013e3181eeda3f.

40. Robicsek A, Suseno M, Beaumont JL, et al. Prediction of Methicillin-Resistant Staphylococcus

aureus Involvement in Disease Sites by Concomitant Nasal Sampling. J Clin Microbiol. 2008 Feb;

46(2): 588–592. doi:10.1128/JCM.01746-07

41. Rioux J, Edwards J, Bresee L, et al. Nasal-Swab Results for Methicillin-Resistant Staphylococcus

aureus and Associated Infections. Can J Hosp Pharm. 2017 Mar-Apr; 70(2): 107–112.

doi:10.4212/cjhp.v70i2.1642

Coco 19

42. Mergenhagen KA, Starr KE, Wattengel BA, et al. Determining the utility of methicillin-resistant

Staphylococcus aureus nares screening in antimicrobial stewardship. Clin Infect Dis. 2019 Oct 1.

pii: ciz974. doi:10.1093/cid/ciz974.

43. Klatt EC. Clinical Laboratory - Fundamentals. Laboratory Medicine Curriculum.

https://webpath.med.utah.edu/ Accessed March, 2020.

44. Maxim LD, Niebo R, Utell MJ. Screening tests: a review with examples. Inhal Toxicol. 2014

Nov;26(13):811-28. doi: 10.3109/08958378.2014.955932.

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Appendix A 42,43

Definitions and formulas for predictive values

Predictive Values

Sensitivity Specificity Positive Predictive

Value (PPV) Negative Predictive

Value (NPV)

Formula 𝑇 +

(𝑇 + (+) 𝐹−)

𝑇 −

(𝑇 − (+) 𝐹+)

𝑇 +

(𝑇 + (+) 𝐹+)

𝑇 −

(𝑇 − (+) 𝐹−)

Simplified meaning

The ability to detect a disease

if it is really present.

The ability to exclude persons who do not have

the disease

How likely is a positive test to

indicate that the person has the

disease

How likely is a negative test to indicate that

the disease is not present in the person

Key: (T+ - True positive), (T- - True negative), (F+ - False positive), (F- - False negative )