What the MRSA PCR? The Role of Nose PCR Swabs in Stewardship.

I recently wrote about the fact that all pneumonia are aspiration events. Depending on the colonization of the oropharynx and the volume of aspirate material plays a role in the development of subsequent disease. It stands to reason that, if we are able to figure out what is colonizing the oropharynx, we may be able to target our antibiotics more appropriately at least on the empiric front. Indeed, this has been attempted for methicillin-resistant staphylococcus aureus. Stewardship programs across the nation have implemented MRSA screening with PCR in those who receive empiric vancomycin for possible HAP/VAP, with negative PCR testing being used to de-escalate anti-MRSA therapy. Indeed, there seems to be a correlation between PCR testing of the nares and subsequent isolation of MRSA in clinical isolates. A prospective study of 1266 patients found that MRSA nasal colonization was 16.4% (1). In multivariate analysis, nasa colonization was associated with increased risk of developing MRSA infection (RR 2.50, 95% CI 1.9-3.27). Another cohort of over 14,000 patients (2) found that colonization of nares was associated with a RR of 3.0 for developing bacteremia (95% CI 2.0-4.7). This was also seen in a cohort of soldiers, with colonization being associated with higher rates of skin-soft tissue infection with MRSA (3).

Obtaining sputum cultures is difficult under the best of circumstances. Initial studies on the implementation of screening evaluated the use of nasal cultures, which tend to have an advantage in its ease of use when compared to sputum cultures, but tend to have a slower turnaround time when compared to its more modern counterpart, the PCR. In a cohort using MRSA nasal culture (4), anti-MRSA therapy was shorter in the intervention group (those who had nasal cultures reported to physicians) compared to the control group (1 day vs 3 days). There was notably, no difference in mortality (14% in control vs 19% in intervention group, p = 0.29). Another cohort compared the nasal culture with PCR (5) in 259 paired samples and found high concordance even when patients took antibiotics, 93.7% in the presence (95% CI 88-96.8%) and 90.9% in the absence (95% CI 84.8%-94.7%) of antibiotics.

Utility of PCR in Relationship to Sputum Cultures

Before going any further, I think it is helpful to put the following data into context. The value of the screening PCR lays on its ability to rule out MRSA pneumonia. Indeed, we are using the assumption that a negative nasal PCR = no colonization and low risk of MRSA pneumonia. If the patient tests positive for nasal MRSA PCR, then who knows what is going on in the lungs. But if they test negative, we can be fairly certain that their pneumonia is not caused by MRSA. Here, we would like to ensure our negative predictive value, the likelihood that someone who tests negative does not have the disease, is as high as possible. It is related to specificity, however while specificity/sensitivity tend to be static numbers that are related to the particular test in question, positive and negative predictive values take into account the disease prevalence (6). Why is this important? Because the PPV and NPV (in particular, the latter which is what we’re focusing) are related to the disease prevalence: 

As you can see, the more common the disease is in your population, then the higher the PPV of that specific test. Indeed, the opposite is true with lower disease prevalence being correlated with higher NPV. Given that MRSA is not quite common, this makes the PCR a good “rule out” tool unless your disease prevalence goes beyond 10% (which is what I was able to find as being the more common prevalence in these studies). Having gotten that out of the way, we can go into a bit more detail about the relationship between nasal PCR and respiratory specimens. In one retrospective study of 435 patients who had either a PCR and a concomitant blood or pulmonary culture (7), the test performed fairly well when the prevalence was 5.7%:

Another retrospective study of 72 patients (8) similarly found good sensitivity/specificity and NPV/PPV, though here there is no mention of prevalence:

In a VA study of 297 paired nasal samples and cultures (9), surveillance MRSA nasal swabs yielded a PPV of 37.5% (95% CI 21.1-56.3) and NPV of 99.3 (95% CI 97.3-99.9%). Sensitivity was 85.7% while specificity was 92.9%. Another retrospective study of 400 critical care patients found a NPV of 99.03, PPV of 37.36, sensitivity 91.89, specificity 84.3% (10). In a similar study, a matched-case control study of 4317 critically ill patients, nasal MRSA cultures yielded a sensitivity/specificity of 72.2% (95% CI 62-81%) and 96.8% (95% CI 96-97%), respectively and PPV and NPV of 32.3% (95% CI 26-39) and 99.4% (99.1-99.6%) when using receipt of vancomycin as a surrogate for suspicion for MRSA (11). A single-center retrospective cohort compared MRSA nasal swab PCR with respiratory culture (12). 200 patients were included, and found that overall, sensitivity and NPV were fairly high (prevalence 10.5%):

While these data seem to suggest a fairly good correlation, one  single-center prospective study enrolling 1083 medical ICU patients,found there was no difference in MRSA infection (either pneumonia or bacteremia) between those who were colonized (27.4%) or not (22.7%) as determined by nasal MRSA cultures (13). Indeed, the sensitivity for swabs that were obtained either at the start or later on during the ICU admission were poor but NPV tended to increase in this population:

The prevalence of MRSA infection in this cohort, however, was 24% which highlights the above point I made about its role in NPV. A meta-analysis that pooled the vast majority of these studies (14) which included over 5160 patients, found that the NPV of MRSA nasal PCR screen was 90.3% when the prevalence was 10%. The NPV increased to 98.1% for CAP/HCAP:

Again, one should note there is a difference in the prevalence of disease and comparators, however in the right population this can be a fairly useful tool to de-escalate antibiotics.

Real-Life Applications:

I am a proponent of hard clinical outcomes. These tend to be either mortality, ICU stay, time in the hospital, etc. Antibiotic use as a primary outcome leaves a lot to be desired and I think this is where I find the data to fall short. Of course, if you implement a study designed to make people use less antibiotics, don’t be surprised when you get a positive result. These can be a bit tricky to design and power to mortality. The data on applicability, however, tends to show the obvious. A retrospective, multicenter study (15) evaluated the implementation of MRSA nasal swab PCR screening by pharmacists for patients who got empiric vancomycin for possible pneumonia. Two implementation periods were evaluated, with median vancomycin duration being shorter after the implementation of MRSA nasal swab PCR to guide therapy (24 hours vs 14.3 hours). A similar single center study of 418 total patients (16) among pre-implementation and post-implementation cohorts found that those in the latter had shorter length of vancomycin duration (1.44 days vs 2.59 days, p < 0.01). Rates of AKI were lower in the post-protocol group (13% vs 24%, p=0.01). Here, the calculated sensitivity, specificity, PPV and NPV were 100%, 95.6%, 36.8% and 100%, respectively. In a study that used both nasal and throat cultures (17), the recommendation to stop vancomycin when both of these were negative was not associated with higher overall in-hospital mortality (7.7%). These are of course helpful data for the stewardship standpoint and allows us to have a tool to prevent overuse of antibiotics, however I would like to see further data on mortality going forward. 

Having said that, it seems that colonization has been looked at as a surrogate for other types of infections. A very thorough review (18) has looked at the role of MRSA nasal swab PCR and subsequent infections including bacteremia. Color me skeptic at this point (I mean, how does nose colonization translate to bacteremia???) but I think it may pan out at the end of the day:

References:

1. Kao KC, Chen CB, Hu HC, Chang HC, Huang CC, Huang YC. Risk Factors of Methicillin-Resistant Staphylococcus aureus Infection and Correlation With Nasal Colonization Based on Molecular Genotyping in Medical Intensive Care Units: A Prospective Observational Study. Medicine (Baltimore). 2015 Jul;94(28):e1100. doi: 10.1097/MD.0000000000001100. PMID: 26181545; PMCID: PMC4617090.
2. Wertheim HF, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JA, van Keulen PH, Vandenbroucke-Grauls CM, Meester MH, Verbrugh HA. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet. 2004 Aug 21-27;364(9435):703-5. doi: 10.1016/S0140-6736(04)16897-9. PMID: 15325835.
3. Ellis MW, Hospenthal DR, Dooley DP, Gray PJ, Murray CK. Natural history of community-acquired methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis. 2004 Oct 1;39(7):971-9. doi: 10.1086/423965. Epub 2004 Sep 2. PMID: 15472848.
4. Raush N, Betthauser KD, Shen K, Krekel T, Kollef MH. Prospective Nasal Screening for Methicillin-Resistant Staphylococcus aureus in Critically Ill Patients With Suspected Pneumonia. Open Forum Infect Dis. 2021 Nov 19;9(1):ofab578. doi: 10.1093/ofid/ofab578. PMID: 34988251; PMCID: PMC8715848.
5. Shenoy ES, Noubary F, Kim J, Rosenberg ES, Cotter JA, Lee H, Walensky RP, Hooper DC. Concordance of PCR and culture from nasal swabs for detection of methicillin-resistant Staphylococcus aureus in a setting of concurrent antistaphylococcal antibiotics. J Clin Microbiol. 2014 Apr;52(4):1235-7. doi: 10.1128/JCM.02972-13. Epub 2014 Jan 22. PMID: 24452168; PMCID: PMC3993487.
6. Parikh R, Mathai A, Parikh S, Chandra Sekhar G, Thomas R. Understanding and using sensitivity, specificity and predictive values. Indian J Ophthalmol. 2008;56(1):45-50. doi:10.4103/0301-4738.37595
7. Dangerfield B, Chung A, Webb B, Seville MT. Predictive value of methicillin-resistant Staphylococcus aureus (MRSA) nasal swab PCR assay for MRSA pneumonia. Antimicrob Agents Chemother. 2014;58(2):859-64. doi: 10.1128/AAC.01805-13. Epub 2013 Nov 25. PMID: 24277023; PMCID: PMC3910879.
8. Johnson JA, Wright ME, Sheperd LA, Musher DM, Dang BN. Nasal methicillin-resistant Staphylococcus aureus polymerase chain reaction: a potential use in guiding antibiotic therapy for pneumonia. Perm J. 2015 Winter;19(1):34-6. doi: 10.7812/TPP/14-101. Epub 2014 Nov 24. PMID: 25432002; PMCID: PMC4315374.
9. Hiett J, Patel RK, Tate V, Smulian G, Kelly A. Using active methicillin-resistant Staphylococcus aureus surveillance nasal swabs to predict clinical respiratory culture results. Am J Health Syst Pharm. 2015 Jun 1;72(11 Suppl 1):S20-4. doi: 10.2146/ajhp140820. PMID: 25991589.
10. Smith MN, Erdman MJ, Ferreira JA, Aldridge P, Jankowski CA. Clinical utility of methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction assay in critically ill patients with nosocomial pneumonia. J Crit Care. 2017 Apr;38:168-171. doi: 10.1016/j.jcrc.2016.11.008. Epub 2016 Nov 15. PMID: 27918901.
11. Chotiprasitsakul D, Tamma PD, Gadala A, Cosgrove SE. The Role of Negative Methicillin-Resistant Staphylococcus aureus Nasal Surveillance Swabs in Predicting the Need for Empiric Vancomycin Therapy in Intensive Care Unit Patients. Infect Control Hosp Epidemiol. 2018 Mar;39(3):290-296. doi: 10.1017/ice.2017.308. Epub 2018 Jan 28. PMID: 29374504.
12. Giancola SE, Nguyen AT, Le B, Ahmed O, Higgins C, Sizemore JA, Orwig KW. Clinical utility of a nasal swab methicillin-resistant Staphylococcus aureus polymerase chain reaction test in intensive and intermediate care unit patients with pneumonia. Diagn Microbiol Infect Dis. 2016 Nov;86(3):307-310. doi: 10.1016/j.diagmicrobio.2016.08.011. Epub 2016 Aug 12. PMID: 27591173.
13. Sarikonda KV, Micek ST, Doherty JA, Reichley RM, Warren D, Kollef MH. 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. PMID: 20683260.
14. Parente DM, Cunha CB, Mylonakis E, Timbrook TT. The Clinical Utility of Methicillin-Resistant Staphylococcus aureus (MRSA) Nasal Screening to Rule Out MRSA Pneumonia: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implications. Clin Infect Dis. 2018 Jun 18;67(1):1-7. doi: 10.1093/cid/ciy024. PMID: 29340593.
15. Woolever NL, Schomberg RJ, Cai S, Dierkhising RA, Dababneh AS, Kujak RC. Pharmacist-Driven MRSA Nasal PCR Screening and the Duration of Empirical Vancomycin Therapy for Suspected MRSA Respiratory Tract Infections. Mayo Clin Proc Innov Qual Outcomes. 2020 Aug 15;4(5):550-556. doi: 10.1016/j.mayocpiqo.2020.05.002. PMID: 33083704; PMCID: PMC7557184.
16. Diep C, Meng L, Pourali S, Hitchcock MM, Alegria W, Swayngim R, Ran R, Banaei N, Deresinski S, Holubar M. Effect of rapid methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction screening on vancomycin use in the intensive care unit. Am J Health Syst Pharm. 2021 Dec 9;78(24):2236-2244. doi: 10.1093/ajhp/zxab296. PMID: 34297040; PMCID: PMC8661079.
17. ​​Boyce JM, Pop OF, Abreu-Lanfranco O, Hung WY, Fisher A, Karjoo A, Thompson B, Protopapas Z. A trial of discontinuation of empiric vancomycin therapy in patients with suspected methicillin-resistant Staphylococcus aureus health care-associated pneumonia. Antimicrob Agents Chemother. 2013 Mar;57(3):1163-8. doi: 10.1128/AAC.01965-12. Epub 2012 Dec 17. PMID: 23254432; PMCID: PMC3591869.
18. Carr AL, Daley MJ, Givens Merkel K, Rose DT. Clinical Utility of Methicillin-Resistant Staphylococcus aureus Nasal Screening for Antimicrobial Stewardship: A Review of Current Literature. Pharmacotherapy. 2018 Dec;38(12):1216-1228. doi: 10.1002/phar.2188. Epub 2018 Oct 29. PMID: 30300441.