Staphylococcus aureus Bacteremia: Contemporary Management

Abstract

Staphylococcus aureus bacteremia (SAB) is a serious cause of bloodstream infection associated with significant morbidity and mortality. Complications include deep-seated foci of infection including infective endocarditis, device-associated infection, osteoarticular metastases, pleuropulmonary involvement, and recurrent infection. With the 30-day all-cause mortality being around 20%, a collaborative effort of early Infectious Diseases (ID) consultation and Antimicrobial Stewardship Program (ASP) involvement will show improved SAB outcomes and therapy optimization.¹

Introduction

Staphylococcus aureus bacteremia (SAB) continues to be a major cause of community and healthcare-acquired bacteremia. While the exact incidence of SAB is difficult to determine, surveillance data from the U.S. shows incidence rates of 20 to 50/100,000.² Rates elsewhere in the industrialized world are reported to be 10 to 30/100,000.³ These discrepancies may be due to the differences in infection control practices, health care systems, accessibility, and adequacy of surveillance data.

In the United States, rates of healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) decreased by 17.1% from 2005–2012. The rate of decline later slowed from 2013–2016. Community-acquired methicillin susceptible Staphylococcus aureus infections (MSSA) conversely, have slightly increased from 2012 to 2017.⁴ Given these data points, institutions are striving to improve their standards on infection control and infection prevention of SAB.

Classification of SAB

Initially, SAB was differentiated into two categories which were healthcare-associated and community-acquired. With differentiation by molecular means and health care exposure with community onset of SAB, the classification of health care-associated community onset was created.⁵ Now SAB is classified into three categories with those being: 1) community-acquired, 2) healthcare-associated community-onset, and 3) healthcare-associated hospital-onset. ⁶

Community-acquired SAB generally refers to those individuals with no previous contact with the health care system. They include injection drug users and spontaneous osteoarticular infections such as vertebral osteomyelitis or epidural abscess. Those with community-acquired SAB are more likely to have greater than one complication such as endocarditis with acute renal failure, shock, acute respiratory distress or disseminated intravascular coagulation on presentation.⁷

Healthcare-associated, community-onset SAB includes those individuals who have constant contact with the healthcare system. These patients include individuals hospitalized in the past 90 days, those receiving intravenous therapy, wound care, or skilled nursing care at home, residence in a long-term acute care facility or nursing home, and those receiving dialysis or chemotherapy.⁶

Healthcare-associated, hospital-onset SAB refers to those acquired in the hospital and include central-line associated bloodstream infections, ventilator-associated pneumonia, and surgical site infections.⁸ Hospital-acquired SAB is more likely to be due to methicillin-resistant strains and is a leading cause of nosocomial bloodstream infection. With the increasing use of intravascular catheters such as port-a-catheters, hemodialysis lines, and peripherally-inserted central catheters, there has been a rising incidence of catheter-associated SAB.

Risk Factors for SAB

Risk factors for SAB include age, underlying medical conditions, injection drug use, presence of intravascular catheters or prosthetic devices and need to be recognized when initially assessing patients.

There have been numerous studies demonstrating age as a determinant of increased SAB incidence. High rates of incidence are seen in the first year of life which decreases in young adulthood but slowly rises with advancing age. The incidence of SAB is 100 per 100,000 person-years among subjects 70 years of age but is only 4.7 per 100,000 person-years in younger, healthier U.S. military personnel.³

The incidence of SAB is also associated with certain underlying medical conditions. In a 21-year longitudinal study done at Duke University from 1995–2015, individuals with diabetes, renal disease dependent on dialysis, rheumatoid arthritis, malignancy history, corticosteroid use, transplant history, and HIV were among the most likely to acquire SAB.⁹ Specifically for the HIV-infected population, lower CD4 count (<100) accounted for an independent risk factor for SAB and among those, injection drug users had the highest burden of SAB.¹⁰

Injection drug users have been found to have a high rate of nasal colonization. Studies have shown those with S. aureus nasal carriage have higher rates of SAB with their colonizing strains.¹¹

Any prosthetic device or indwelling catheter remains a foreign body and possible nidus for infection. The Duke University longitudinal study revealed more than half of the enrolled patients had an implantable device such as a central vascular catheter, pacemaker/ defibrillator, prosthetic valve, endovascular prosthesis, or arthroplasty, which served as their source of SAB.⁹ Intravascular catheter is the most common cause of hospital-acquired SAB.

Complicated SAB

SAB is notorious for having varied sources of causation. Common sources include catheter-related, pleuropulmonary, osteoarticular, and heart valve. SAB may be further classified as complicated or uncomplicated. The Infectious Diseases Society of American (IDSA) has defined uncomplicated SAB as those in which there is: exclusion of endocarditis, no implanted prostheses, negative follow-up blood cultures drawn two to four days after the initial set, defervescence within 72 hours after initiating appropriate antibiotic therapy, and no evidence of metastatic infection.¹² In a prospective, observational cohort study done in the late 1990s, patients were followed up to 12 weeks after an initial positive blood culture result. Complications included central nervous system involvement, embolic phenomena, metastatic site of infection or recurrent infection within 12 weeks. Predictors of complicated SAB were community acquisition, persistent positive blood cultures at 48 to 96 hours, persistent fever at 72 hours, and skin findings suggestive of systemic infection.¹³

Diagnostic Evaluation of SAB

In general, blood cultures returning positive for Staphylococcus aureus should initiate prompt clinical evaluation and initiation of empiric antibiotic therapy. A thorough history and physical are essential in providing information on the source of bacteremia and evidence of any suggestion of metastatic infection.

Imaging for metastatic disease should be tailored according to symptoms. Assessing for back pain indicating possible vertebral osteomyelitis or discitis, abdominal pain indicating possible renal or splenic infarct, headaches or vision changes for metastatic CNS manifestations are just a few examples of evaluating the extent of disease.¹⁴

Most patients with positive blood cultures for SAB undergo transthoracic echocardiogram (TTE) to investigate for potential endocarditis if the risk is high and the source is not apparent. The use of routine transesophageal echocardiogram (TEE) is more controversial. While it has increased sensitivity, the costs, risks and availability should be considered. Generally, if a patient is considered to have low risk of endocarditis on the basis of a negative TTE, nosocomial acquisition of SAB, clearance of bacteremia <72 hours, absence of intracardiac device or prosthetic valves, absence of hemodialysis dependence, and no clinical signs of metastatic disease or endocarditis, TEE may not be required.¹⁵

Intravascular catheter is the most common cause of hospital acquired Staph aureus bacteremia.

Management of SAB

All patients with uncomplicated SAB are recommended to receive at least two weeks of intravenous antibiotic therapy. For complicated SAB, therapy with intravenous antibiotics for four to six weeks has been the standard practice.¹⁶ The selection of antibiotic is dependent on methicillin susceptibility. Agents used for treatment of MSSA include penicillinase-resistant semisynthetic penicillins, first-generation cephalosporins, vancomycin and daptomycin.¹⁷ A beta-lactam is the preferred drug of choice for MSSA bacteremia. Anti-staphylococcal penicillins such as nafcillin are often utilized as first line agents. Concern with frequency of dosing and adverse effects of nephrotoxicity and neutropenia have led to interest in alternative beta-lactams. Cefazolin is a first-generation cephalosporin with a favorable pharmacokinetic profile and less frequent dosing. In vitro data suggests an inoculum effect can occur resulting in high rates of antibiotic failure for treatment of MSSA infection with high bacterial inoculum.¹⁸ Despite this in vitro data, the impact of the inoculum effect in the clinical scenario is controversial.¹⁹ There have been several retrospective cohort studies comparing anti-staphylococcal penicillins to cefazolin treatment. In a large retrospective cohort study done in Australia from January 2007 to September 2013, mortality was compared in patients with MSSA bacteremia treated with flucloxacillin to those treated with cefazolin. It found there was no difference in 30-day mortality. It suggested cefazolin is equivalent or superior to anti-staphylococcal penicillins but that randomized controlled trial data are lacking.²⁰

In the case of MRSA bacteremia, vancomycin or daptomycin monotherapy is recommended as first line agents.¹² Vancomycin is a glycopeptide that inhibits cell wall synthesis. It has been questioned on its efficacy profile and adverse effects. There have been concerns of poor tissue penetration, slow bactericidal activity, resistance issues, inability to achieve adequate drug levels, and nephrotoxicity.²¹ Daptomycin is a cyclic lipopeptide that causes depolarization of the bacterial cell membrane. It was seen to have similar efficacy to standard therapy for both MSSA and MRSA bacteremia.²² Adverse effects of myopathy, eosinophilic pneumonia and the lack of efficacy in MRSA pneumonia preclude its use in certain clinical situations.

Treatment failure defined as persistent MRSA bacteremia for seven days or more is of concern and should prompt evaluation of whether a change in therapy is required. IDSA guidelines recommend an assessment for foci of infection that may need surgical attention and/or consideration of high dose daptomycin in combination with another agent such as gentamicin, rifampin, linezolid, or a beta-lactam antibiotic.¹² Combination therapy with vancomycin and gentamicin or rifampin has been associated with adverse effects such as nephrotoxicity and drug interactions. In a recently published randomized clinical trial, combination therapy with beta-lactams also showed no significant improvement in mortality.²³ Patients were randomized to standard therapy (vancomycin or daptomycin) plus an anti-staphylococcal beta-lactam (flucloxacillin, cloxacillin, or cefazolin) for seven days or standard therapy alone. The study was stopped early as there was a high incidence of acute kidney injury with combination therapy. It demonstrated the addition of anti-staphylococcal beta-lactam to vancomycin or daptomycin did not result in improvement in the end point of 90-day mortality, persistent bacteremia, relapse or treatment failure.²³

Ceftaroline, a beta-lactam that has activity against MRSA has been studied in a preliminary manner in combination with daptomycin with a suggestion of better efficacy when compared to vancomycin monotherapy.²⁴ Similarly, in a retrospective matched cohort design study, those who received a combination of daptomycin and ceftaroline were compared to monotherapy with vancomycin.²⁵ Mortality rates were similar in the two groups even though patients on combination therapy had higher rates of persistent bacteremia at study entry, and questioned whether receiving combination therapy at the start of therapy could be beneficial. Blinded, randomized controlled studies are needed to study combination therapies.

Guidelines emphasize empiric treatment, repeating blood cultures to document clearance of bacteremia and narrowing to appropriate therapy once cultures have finalized. Recent studies have demonstrated the concern for inappropriate therapy selection, delayed response time in choosing appropriate therapy, and failure in recognizing associated complications may lead to increased detrimental outcomes.^26,27 Infectious Diseases consultations (IDC) improve SAB outcomes including a reduction in mortality, complication rates, and relapse. In a study done at Dartmouth-Hitchcock Medical Center, 240 patients with SAB were selected to be evaluated.²⁶ Of those, 122 patients received IDC. The observed characteristics between both groups were similar. Those who received IDC were advanced in age and more likely to have health care-associated SAB. Those who received Infectious Disease consultation had more appropriate antimicrobial selection and monitoring of positive blood cultures, intravascular catheter/device removal (if needed), and lower mortality. Another study done at Barnes-Jewish Hospital between 2005–2007 evaluated the 28-day all-cause mortality and 365 day all-cause mortality to assess the efficacy of IDC for SAB.²⁷ IDC was associated with 56% reduction in all-cause mortality in SAB patients within 28 days of the positive blood culture. Those who had IDC were more likely to have received appropriate antibiotic therapy, evaluation by TEE, and appropriate planned duration of antimicrobial therapy.²⁷

In addition to IDC, clinical guidance by Antimicrobial Stewardship Programs are well positioned to influence SAB outcomes. Collectively, joint efforts between IDC and ASP can improve care and outcomes. In one study, lack of ASP intervention was associated with suboptimal management in 20% of cases, including use of vancomycin for MSSA bacteremia, inappropriate use of oral antimicrobial therapy, and absence of any antimicrobial therapy.²⁸ ASPs have shown benefit by closely monitor microbiologic data and decreasing the time between effective and de-escalated therapy. The clinical course of SAB prior to and post implementation of rapid polymerase chain reaction (rPCR) testing for Staphylococcus aureus and methicillin resistance with ASP involvement was compared in a study at the Ohio State University Medical Center.²⁹ A pharmacist from the ASP was contacted with the result of the rPCR and immediately recommended IDC and appropriate antibiotics. rPCR testing with ASP was associated with earlier appropriate antimicrobial usage, a lower mean length of stay and lower hospital costs.

Conclusion

SAB continues to be a major cause of bloodstream infection worldwide. Incidence rates of community-onset MSSA bacteremia have increased. Appropriate use of IDC and ASP may improve selection of antimicrobial therapy, response time, and management and recognition of complications of SAB that may improve outcomes.