S aureus Bacteremia Management Requires Antimicrobial Stewardship From All Health Care Professionals

Staphylococcus aureus is the most frequent cause of community- and hospital-acquired bacteremia in North America. S aureus most commonly colonizes the nares and may spread to the blood, resulting in S aureus bacteremia (SAB).^1-3 SAB is a burden on the health care system because it is becoming increasingly difficult to manage and is associated with increased mortality. Additionally, approximately 25% of hospital staff are carriers of S aureus.² The incidence rate of SAB is 20 to 30 cases per 100,000 individuals and has risen over the years, specifically in older adults, as methicillin-resistant S aureus (MRSA) has become more prevalent.^2,3

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Risk Factors

Risk factors for SAB include colonization with S aureus, intravenous (IV) drug use, use of prosthetic heart valves, and intravascular device use. Factors that put individuals at increased risk of SAB are type 1 diabetes, renal hemodialysis, recent vancomycin treatment, MRSA infection, and persistent bacteremia. Early identification of SAB may be beneficial because it allows for expeditious infectious disease consultation and initiation of appropriate therapy.³

Complicated SAB

Patients at increased risk of complicated SAB include individuals who have a positive repeat follow-up blood culture result in 48 to 96 hours following initial positive culture result, vascular catheters or indwelling devices, constant fever following 3 days after initial presentation, and skin lesion(s) indicative of an acute systemic infection. Complications associated with persistent SAB following initiation of empiric antibiotic therapy include a 30-day mortality rate that is nearly double that of individuals for whom blood culture results have cleared. A more severe complication associated with SAB is infective endocarditis (IE), which is a result of S aureus colonization on the lining, valves, and/or blood vessels of the heart. Additionally, SAB may lead to the development of metastatic infections.^1,2

Diagnosis

Blood cultures are employed to detect the presence of S aureus. One positive culture result is considered significant enough to initiate empiric therapy while concurrently continuing to evaluate the patient. Follow-up cultures should be collected every 24 to 48 hours until S aureus is no longer detectable in the blood. If a patient has continued bacteremia despite empiric therapy, the patient will require additional evaluation. A thorough evaluation of patient history must be completed alongside a physical examination.¹

Additionally, an echocardiogram may be conducted to assess the presence of vegetation. A transthoracic echocardiography (TTE) is generally performed first. Presence of vegetation on the TTE suggests the need to perform a transesophageal echocardiography (TEE), which is more sensitive to the presence of valvular vegetation; however, this procedure may lead to esophageal perforation. A TEE should be performed if the SAB continues despite antimicrobial therapy and the duration of infection is unknown as well as if there is cardiac prosthetic material or predisposing valvular abnormality, dependency on hemodialysis, and/or IV drug use. Individuals are more susceptible to forming vegetation on valves 5 to 7 days following onset of SAB. Symptoms that may indicate the need for additional imaging include back pain (evaluate for vertebral osteomyelitis or prostate-specific antigen), abdominal pain (evaluate for splenic and/or renal infarct), and headache (evaluate for soft tissue damage).^1,2

Infective Endocarditis

Although a rare condition associated with SAB, IE can greatly increase the morbidity and mortality associated with SAB. IE may be the primary source of SAB from a secondary metastatic complication where valves are seeded from an extracardiac source. Broadly, IE refers to an infection on the surface of the heart, commonly associated with a valve surface (native or prosthetic) or an infection involving an intracardiac device (Table 3). IE can be further stratified into right-sided or left-sided IE, with left-sided being the more common presentation. Because of the wide variability in presentation and need for rapid diagnosis, strategies have been designed to aid practitioners in diagnosing the disease and determining the need for echocardiograms.^2,4,5

Table 1: Major criteria | FDG-PET, fluorodeoxyglucose-positron emission tomography; IE, infective endocarditis; IFS, interfering factors screen; PCR, polymerase chain reaction.

Duke-International Society for Cardiovascular Infectious Diseases Criteria

Because of IE’s variable presentation and need for rapid diagnosis, strategies are needed to aid in IE’s diagnosis among all disease forms. Initially published in 1994 and most recently updated in 2023, the Duke-International Society for Cardiovascular Infectious Diseases criteria utilize major and minor clinical criteria to aid in the formal diagnosis of IE by stratifying patients into categories of rejected, possible, or definite. The clinical criteria for definite and possible categorization rely on the major and minor criteria seen in Tables 1 and 2. A patient may meet the definite category through pathological or clinical criteria.^6-8

Table 2: Minor criteria | CIED, cardiovascular implantable electronic device; FDG-PET, fluorodeoxyglucose–positron emission tomography; IE, infective endocarditis.

Pathological criteria involve either visualization or culture data direct from vegetation. To be categorized as definite based on clinical criteria, a patient must meet 2 major, 1 major and 3 minor, or 5 minor criteria. The possible designation solely relies on the major and minor clinical criteria. A possible categorization occurs if the patient meets 1 major and 1 minor or 3 minor criteria. For a patient to be placed in the rejected category, another diagnosis explaining the symptoms is present, there is not recurrence with less than 4 days of antibiotics, there is no pathologic or macroscopic evidence of IE during surgery/biopsy, and the patient cannot be otherwise classified as possible.^6,8

Table 3: Common pathogens | HACEK, Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae. | †Added in 2023 update.

VIRSTA Score

Recommendations for TEE are not consistent within the SAB literature. Even in cases where TEE may be recommended for patients with SAB, it still is not performed in a significant number of patients. The VIRSTA score (Table 4) predicts the risk of IE within 48 hours of SAB diagnosis and can be used to determine the need for TEE. Consisting of 10 yes/no questions with correlated point values, VIRSTA places patients into high- and low-risk categories. A score of 3 or more points indicates high risk and may be grounds for urgent TEE. The VIRSTA score has been externally validated to show a high negative predictive value of up to 98.9% (original cohort, 95.3%). A negative VIRSTA score (< 3 points) has shown a probability of IE of less than 1% (0.4%). Cost-effectiveness studies have shown a possible lack of utility of obtaining a TEE if the risk of IE is less than 1% due to the lack of cost or survival benefit. A negative VIRSTA score may justify deferring TEE, decreasing patient risk and cost.⁹

Table 4: Virsta score | IE, infective endocarditis; IV, intravenous.

Guideline-Driven Treatment

Selection of appropriate therapy should be dependent upon culture and susceptibility reports.¹ Until culture and susceptibility results have been received, empiric treatment should be initiated for MRSA. Vancomycin is the mainstay treatment option commonly utilized; however, daptomycin may be an alternative. If susceptibility results are suggestive of methicillin-sensitive S aureus (MSSA), treatment should be de-escalated. First-line treatment for MSSA consists of β-lactam agents inclusive of nafcillin, oxacillin, and cefazolin to maximize kill time.^1,7 An issue with cefazolin and high inoculum infections is a possible cefazolin inoculum effect. This effect causes the cefazolin minimum inhibitory concentration to be elevated in proportion to the number of bacteria in the inoculum and has been associated with therapeutic failures and mortality in invasive MSSA infections.¹⁰

Complicated MRSA bacteremia may require escalation to other antibiotics, such as daptomycin or ceftaroline. The landscape of SAB treatment is changing. Findings from the phase 3 ERADICATE study (NCT03138733) showed that implementation of a MRSA bacteremia treatment pathway with early use of a β-lactam reduced mortality with no increased rate of acute kidney injury.11 The addition of ertapenem to cefazolin has been used to salvage cases of severe MSSA bacteremia.¹² A summary of treatment options is available in Table 5.

Table 5: Treatment options for MRSA bacteremia | IV, intravenous; IVDA, intravenous drug abuse; MRSA, methicillin-resistant Staphylococcus aureus; TTE, transthoracic echocardiography. | *Assuming normal renal function.

The duration of therapy is generally 14 days; however, that is based upon the etiology and severity of the infection. Patients at high risk may benefit from extended course of antibiotics (21-42 days once blood cultures show negative results).^1,7 The treatment pathways are evolving, and new guidelines are much needed to display this change.

The Skip Phenomenon

Current Infectious Diseases Society of America guidelines suggest a single set of negative blood culture results are adequate evidence of SAB clearance. Several studies have identified the skip phenomenon, which is the occurrence of intermittent negative blood culture results, while managing SAB. Some experts recommend obtaining additional blood cultures to document bacterial clearance, such as 2 sets of negative blood culture results.¹³

Antibiotics: IV or Oral?

The decision of when to change from IV to oral antibiotics has been an area of interest for some time. At least 14 days of IV antibiotic treatment are recommended under current guidelines for SAB. But findings from recent studies have shown that transition from IV to highly bioavailable oral antibiotics was not inferior in selected patients. The SABATO study is a randomized trial (NCT01792804) examining the efficacy and safety of early oral switch therapy in low-risk S aureus infection.^13,14

Role of the Pharmacist

Not only is it the duty of pharmacists to serve as antimicrobial stewards, but all health care professionals should be charged with being stewards as well. As the medication expert, it should be the responsibility of the pharmacist to review and ensure the appropriateness of antibiotic regimens. Pharmacists need to be aware of how to optimize dosing of these antibiotics and of potential adverse events. Keeping up with changes in literature is also very important to ensure optimal antibiotic stewardship. SAB is a complicated disease state with a high mortality rate. Pharmacists play a vital role in improving patient outcomes.^15,16

References

1. Fowler VG Jr, Holland TL. Clinical approach to Staphylococcus aureus bacteremia in adults. UpToDate. Updated September 29, 2023. Accessed October 20, 2023. https://www.uptodate.com/contents/ clinical-approach-to-staphylococcus-aureus-bacteremia-in-adults

2. Naber CK. Staphylococcus aureus bacteremia: epidemiology, pathophysiology, and management strategies. Clin Infect Dis. 2009;48(suppl 4):S231-S237. doi:10.1086/598189

3. Kern WV, Rieg S. Burden of bacterial bloodstream infection-a brief update on epidemiology and significance of multidrug-resistant pathogens. Clin Microbiol Infect. 2020;26(2):151-157. doi:10.1016/j.cmi.2019.10.031

4. Holland TL, Baddour LM, Bayer AS, Hoen B, Miro JM, Fowler VG Jr. Infective endocarditis. Nat Rev Dis Primers. 2016;2:16059. doi:10.1038/nrdp.2016.59

5. Grapsa J, Blauth C, Chandrashekhar YS, et al. Staphylococcus aureus infective endocarditis: JACC Patient Pathways. JACC Case Rep. 2021;4(1):1-12. doi:10.1016/j.jaccas.2021.10.002.

6. Baddour LM, Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-1486. doi:10.1161/CIR.0000000000000296

7. Alosaimy S, Lagnf AM, Morrisette T, et al. Standardized treatment and assessment pathway improves mortality in adults with methicillin-resistant Staphylococcus aureus bacteremia: STAPH study. Open Forum Infect Dis. 2021;8(7):ofab261. doi:10.1093/ofid/ofab261

8. Fowler VG, Durack DT, Selton-Suty C, et al. The 2023 Duke-International Society for Cardiovascular Infectious Diseases criteria for infective endocarditis: updating the modified Duke criteria. Clin Infect Dis. 2023;77(4):518-526. doi:10.1161/CIR.0000000000000296

9. Peinado-Acevedo JS, Hurtado-Guerra JJ, Hincapié C, et al. Validation of VIRSTA and Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT) scores to determine the priority of echocardiography in patients with Staphylococcus aureus bacteremia. Clin Infect Dis. 2021;73(5):e1151-e1157. doi:10.1093/cid/ciaa1844

10. Rincon S, Carvajal LP, Gomez-Villegas SI, et al. A test for the rapid detection of the cefazolin inoculum effect in methicillin-susceptible Staphylococcus aureus. J Clin Microbiol. 2021;59(4):e01938-20. doi:10.1128/JCM.01938-20

11. Hamed K, Engelhardt M, Jones ME, et al. Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, phase III trial. Future Microbiol. 2020;15(1):35-48. doi:10.2217/fmb-2019-0332.

12. Ulloa ER, Singh KV, Geriak M, et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2020;71(6):1413-1418. doi:10.1093/cid/ciz995

13. Go JRU, Baddour LM, Lahr B, Sohail MR, Palraj R. 9. the skip phenomenon in Staphylococcus aureus bacteremia: clinical associations. Open Forum Infect Dis. 2021;8(suppl 1):S7-S8. doi:10.1093/ofid/ofab466.009

14. Jorgensen SCJ, Lagnf AM, Bhatia S, Shamim MD, Rybak MJ. Sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteraemia: one step closer. J Antimicrob Chemother. 2019;74(2):489-498. doi:10.1093/jac/dky452

15. Kaasch AJ, Fätkenheuer G, Prinz-Langenohl R, et al; SABATO Trial Group. Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial. Trials. 2015;16,450. doi:10.1186/s13063-015-0973-x

16. Parente DM, Morton J. Role of the pharmacist in antimicrobial stewardship. Med Clin North Am. 2018;102(5):929-936. doi:10.1016/j.mcna.2018.05.009

About the Authors

Kennadi K. Johnson is a 2024 PharmD candidate of William Carey University School of Pharmacy in Biloxi, Mississippi. Her professional interests include infectious diseases, cardiovascular conditions, oncology, and psychiatric conditions.

Ron Welch, PharmD, BCPS, BCID, is a clinical lead specialist at Baptist Memorial Hospital- Golden Triangle in Columbus, Mississippi. He specializes in cardiology and infectious disease.

Robert Martin, PharmD, BCPS, is a clinical pharmacist at Baptist Memorial Hospital-Golden Triangle in Columbus, Mississippi. He specializes in internal/adult medicine.