Antibiotic Options for MRSA Bacteremia: Are We Still Stuck in “Mississippi Mud?”

Staphylococcus aureus bacteremia (SAB) has been a constant and growing problem in different communities and health care settings. One of the biggest issues is that SAB usually is associated with deep-seated invasive infections that tend to recur if not properly eradicated.¹ Methicillin-resistant S aureus (MRSA) bacteremia has been shown to have worse clinical outcomes than methicillin-susceptible S aureus (MSSA) bacteremia.² Due to the large health care burden imposed by SAB, different antibiotics have been used to address this issue and new antibiotics are being evaluated as an option for MRSA bacteremia. This article reviews the current standard of therapy for MRSA bacteremia as well as alternative antibiotic options and the evidence for their use.

VANCOMYCIN
Vancomycin has been the gold standard therapy for MRSA bacteremia for decades as well as empirical therapy for possible gram-positive infections. It is amazing to think that it was introduced in 1958³ yet remains widely used in an array of clinical settings. Although some would attest to its reliability even today, several studies show high rates of treatment failure, particularly with complicated MRSA bacteremia.³ Vancomycin primarily acts by inhibiting cell wall synthesis by interfering with peptidoglycan synthesis by binding to the D-alanyl-D-alanine terminus, preventing transpeptidation, and subsequent cross-linking of the cell wall leading to cell death. This makes it an effective, albeit slow, bactericidal agent for MRSA, reaching bactericidal threshold by 24 to 72 hours after administration.^3,4 In contrast, daptomycin and β-lactams can reach their bactericidal threshold within a few hours.³ There is an ongoing debate regarding vancomycin use as the drug of choice for MRSA bacteremia due to concerns about worse outcomes with elevated vancomycin minimum inhibitory concentration (MIC) and difficulty with therapeutic drug monitoring. Previous studies have suggested a correlation between elevated vancomycin MIC and worse clinical outcomes, including increased mortality, in S aureus infections. Although the specific MIC cutoffs are not uniformly reported (MIC > 1 μg/mL vs MIC ≥ 1.5 μg/mL vs MIC > 2 μg/mL), the overall trend seems to show the importance of considering MIC levels in clinical decision-making.^5,6

Infectious Diseases Society of America guidelines recommend that for vancomycin MIC of 2 μg/mL or more, an alternative antibiotic should be chosen; for those with MIC of 2 μg/mL or less, the patient’s clinical and microbiologic response should dictate continued vancomycin use.⁷ This was underscored by 2 meta-analyses, both published in 2012, that showed high vancomycin MIC (> 1 μg/mL and ≥ 1.5 μg/mL, respectively) is associated with worse outcomes.^5,6 Since then, additional systematic reviews and meta-analyses have showed mortality and worse outcomes are not associated with high vancomycin MIC.^2,8

A more recent meta-analysis by Ishaq et al showed that overall mortality and complicated bacteremia were not significantly associated with high vancomycin MIC in a patient with MRSA bacteremia and that more randomized clinical trials (RCTs) are needed to assess the utility of vancomycin MIC values in predicting mortality and other adverse outcomes.² Although differing conclusions exist, these findings highlight the importance of considering MIC levels in the management of S aureus infections, particularly MRSA bacteremia.

Further research including RCTs with standardization in MIC reporting and an individualized approach to patient care are warranted to properly define treatment strategies based on vancomycin MIC alone. Therapeutic drug monitoring with vancomycin has since moved away from vancomycin trough levels and shifted toward use of the area under the curve (AUC)/ MIC ratio because it allows a more precise way of monitoring vancomycin levels that maintains efficacy while minimizing the risk of acute kidney injury.⁹ Not all facilities have access to AUC/MIC monitoring, limiting its use to larger or academic-based institutions. Vancomycin-associated nephrotoxicity (VAN) has been widely reported since vancomycin was introduced in 1958, with incidence ranging from 5% to 43%.¹⁰ A meta-analysis showed that the strength of evidence that vancomycin is associated with higher risk of kidney injury was judged to be moderate with relative risk of 2.45 and attributable risk percentage of 59%.¹¹ The time to kidney injury was noted to be 4 ± 3 days with about 90% having partial recovery and 33% having full recovery of kidney function.¹²

The pathophysiology of VAN is not well understood, but accumulation of vancomycin in the tubular epithelial cells’ cytoplasm plays an essential role in inducing oxidative stress, complement activation, inflammatory injury, mitochondrial dysfunction, and cellular apoptosis in the proximal renal tubules.¹² Vancomycin has also been associated with IgE-mediated and IgE-independent hypersensitivity reactions. The latter is known as red man syndrome, which is a benign reaction during vancomycin infusion mediated by IgE-independent mast cell and basophil degranulation and can be addressed by premedication and slower infusion rates.

Both immediate IgE-mediated reactions (including anaphylaxis) and nonimmediate reactions can also occur (eg, antibiotic-associated drug rash eosinophilia and systemic symptoms syndrome, maculopapular rash, linear IgA bullous dermatosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.)¹³ Because of challenges in vancomycin therapeutic drug monitoring, differing conclusions on how to manage elevated vancomycin MIC, and associated adverse effects, alternative antibiotics have been suggested as the drug of choice for MRSA bacteremia.

DAPTOMYCIN
Daptomycin is a cyclic lipopeptide antibiotic that is rapidly bactericidal against MSSA and MRSA.³ It works by calcium-dependent direct insertion into and disruption of the functional integrity of the bacterial cell membrane, causing rapid loss of membrane potential, cessation of macromolecular synthesis, and cell death.^14,15 In contrast to vancomycin, daptomycin does not need any therapeutic drug monitoring, making it a very enticing alternative to vancomycin. Despite its bactericidal activity and excellent skin and soft tissue penetration, daptomycin has been shown to be clinically ineffective in bronchoalveolar pneumonia (BAP).^14,15 An in vitro model study looking at the clinical efficacy of daptomycin in BAP showed no detectable reduction in bacterial burden at 24 hours after infection. In contrast, daptomycin seems to be effective in hematogenous pneumonia that occurs because of bacteremia (eg, septic emboli from infective endocarditis [IE]).¹⁵

The lack of efficacy of daptomycin in BAP stems from the interaction of daptomycin and pulmonary surfactant (PS) that coats the interior surface of the airway. Both PS and gram-positive bacteremia contain phosphatidylglycerol, which enhances daptomycin insertion. Thus, daptomycin is unable to effectively differentiate between PS and the bacterial cell membrane, causing it to be irreversibly sequestered in the surfactant layer and rendering it ineffective.¹⁵ It is currently approved for use in complicated skin and soft tissue infections and SAB including right-sided IE, but it has also been used for bone and joint infections and prosthetic joint infections with good clinical outcomes.^16,17 An open-label, randomized trial (NCT00093067) looked at patients with SAB ± IE to receive either 6 mg/kg of daptomycin daily or initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin.¹⁴ The incidence of MRSA in both groups is comparable (37.5% vs 38.3%). About 50% of participants are classified as having complicated bacteremia in both groups, each with about 10% right-sided IE and 8% left-sided IE.

Daptomycin has shown to be noninferior to standard therapy for SAB and right-sided IE. It is important to note that therapy failed in all patients with left-sided endocarditis caused by MRSA.¹⁴ The study by Fowler et al has helped establish the dose of 6 mg/kg daily as the standard dosing for daptomycin, but experts suggest higher doses are warranted in invasive gram-positive infections, particularly SAB. The rationale for high dosing of daptomycin is based on the maximum concentration to MIC ratio and AUC/MIC ratio. To achieve its PK/PD targets, a higher dose than 6 mg/kg might be required particularly since daptomycin observes dose-dependent killing.^18,19 In fact, doses of up to 12 mg/kg have been shown to be efficacious and are rarely associated with higher creatine kinase elevation.^19,20 Given published and clinical experience with doses of 8 to 12 mg/kg per day, adopting this dose particularly for severe and invasive infections, particularly with S aureus, would be reasonable. Daptomycin is associated with muscle toxicity presenting as myositis and rhabdomyolysis requiring regular clinical and creatine kinase monitoring, especially for those on long-term treatment.^18,19 Eosinophilic pneumonitis has also been reported but the exact mechanism of daptomycin toxicity to the lungs remains unknown, although several theories include epithelial injury and inflammation as well as increased eosinophil production and migration to the lungs.²¹

CEFTAROLINE
Ceftaroline is the active metabolite of ceftaroline fosamil and an advanced-generation cephalosporin that has activity against MSSA and MRSA. It inhibits cell wall synthesis by binding to penicillin-binding proteins, particularly having high affinity to penicillin-binding protein 2a, a protein encoded by the mecA gene that determines methicillin resistance.²² It is approved by the FDA for acute bacterial skin and skin-structure infections (ABSSSI) with or without bacteremia, and community-acquired bacterial pneumonia (CABP).²³ It is not approved for primary MRSA bacteremia although it has been used off label for such indication with success, as well as salvage therapy in combination with daptomycin due to its ability to retain activity to MRSA despite reduced susceptibility to vancomycin and daptomycin (“seesaw effect”).²⁴

A multicenter cohort study of 270 patients divided between ceftaroline (n = 83) and daptomycin (n = 187) for MRSA bacteremia compared 30-day mortality, duration of bacteremia at 7 days or more, and 60-day MRSA bacteremia recurrence; the study showed no statistically significant differences in the outcomes assessed. Most of the sources of bacteremia for both cohorts are endovascular (34.9% vs 34.8%) followed by bone and joint (33.7% and 29.9%). Given that these are considered severe and invasive infections, the results of the study showed potential of ceftaroline as an alternative antibiotic for MRSA bacteremia. The authors of the study pointed out that the study is observational, and thus conclusion of noninferiority may not be definitive and generalizability is limited.²⁵

Given the lack of a more robustly designed RCT to support its use for MRSA bacteremia as initial therapy or monotherapy, the role of ceftaroline in SAB for now seems limited to those cases where the source of bacteremia is either ABSSSI or CABP, as part of combination salvage therapy, or in those patients who are unable to take vancomycin or daptomycin. CEFTOBIPROLE Ceftobiprole, like ceftaroline, is an advanced-generation cephalosporin that is bactericidal against MSSA and MRSA. ERADICATE (NCT03138733) is a phase 3, double-blind, noninferiority trial (15% inferiority margin) comparing ceftobiprole vs daptomycin for treating complicated SAB, including right-sided IE; the study was published in the New England Journal of Medicine in September 2023.²⁶ It included 387 patients (189 ceftobiprole, 198 daptomycin) with SAB (23.8% MRSA vs 24.7% MRSA). There were 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group who had overall treatment success 70 days after being randomly assigned; success was defined as survival, bacteremia clearance, symptom improvement, no new SAB-related complications, and no receipt of other potentially effective antibiotics. Soft tissue infections were the major source of bacteremia (61% in both groups) followed by osteoarticular infections. Right-sided IE was only present in 7.9% with ceftobiprole and 5.1% with daptomycin. Although not FDA approved for use in the United States, the FDA did accept a new drug application for ceftobiprole, and it is a candidate for the US Generating Antibiotic Incentives Now Act. The results of ERADICATE showed promise in treating SAB.²⁷ Its role in primary MRSA bacteremia or those with more invasive or severe disease, particularly IE, remains unclear without further studies in these populations.

DALBAVANCIN
Dalbavancin is a lipoglycopeptide that has activity against MSSA and MRSA. It is unique among antibiotics listed here because it has a long half-life, allowing it to be administered once a week.^22,28 It is FDA approved for use in adults and children only for treatment of ABSSSI caused by MSSA/MRSA, Streptococcus species (including Streptococcus pyogenes and Streptococcus anginosus), and vancomycin-susceptible Enterococcus faecalis.²⁹ Multiple studies have shown favorable outcomes with osteomyelitis and prosthetic joint infection.^30,31 Its role in SAB has been investigated through a retrospective cohort study of 225 patients with SAB (45 dalbavancin, 180 standard of care).²⁸ The 90-day clinical failure between the dalbavancin group and the standard-of-care group was similar. The incidence of MRSA was similar in both groups (37.3% overall, 36.1% standard of care, 42.4% dalbavancin).

The dalbavancin group had a higher incidence of community-acquired infection and persons who use drugs compared with the standard-of-care therapy group. Skin and soft tissue infections were a major source of bacteremia (35.6%) followed by musculoskeletal source (24.4%). Only 13.3% had endocarditis (14.4% standard of care, 8.9% dalbavancin). The majority of the dalbavancin group only received 1 dose (82.2% vs 2 doses, 17.8%). The diagnosis of complicated SAB was made in 54.7% of the participants, with the standard-of-care group having numerically higher incidence (57.2% vs 44.4%).

The median duration of standard of care antibiotics administered before dalbavancin is 15 days.²⁸ Note that the recommended duration of therapy for uncomplicated SAB is 14 ± 2 days.³² This means that the majority of patients with uncomplicated SAB in the dalbavancin group effectively received 3 to 4 weeks of treatment (2 weeks of standard-of-care antibiotics and at least 1 dose of dalbavancin), which is longer than what is normally recommended with these types of infections. This could affect the overall efficacy and conclusions of the study. Despite dalbavancin’s limited FDA-approved indication, the American Heart Association released a scientific statement to offer a longacting lipoglycopeptide such as dalbavancin as a best practice option for all patients who cannot complete 6 weeks of intravenous (IV) treatment, regardless of reason. The recommended regimen is either 1000 mg IV loading dose, then 500 mg IV weekly, or 1500 mg IV loading dose and 1000 mg IV every other week.³³ The ongoing phase 2b, multicenter, open-label, superiority DOTS trial (NCT04775953) will compare the desirability of outcome ranking at day 70 for patients randomly assigned to dalbavancin vs standard of care. The study will include patients with complicated SAB, including definite or possible right-sided IE, who have been treated with effective antibiotic therapy for at least 72 hours and with subsequent clearance of bacteremia prior to random assignment.³⁴ As of October 3, 2023, the study had completed its enrollment.³⁵ Results of this study could provide more insight regarding the role of dalbavancin in SAB. Dalbavancin’s once-a-week administration makes it an appealing alternative to daily IV antibiotics, particularly for those not eligible for central line placement (ie, persons who inject drugs). At this time, the use of dalbavancin for MRSA bacteremia needs to be weighed based on the risks and benefits of the patient, as well as determining the circumstances for which it is best suited.

LINEZOLID
Linezolid is an oral oxazolidinone that has activity against MSSA and MRSA with virtually 100% oral bioavailability; excellent tissue penetration makes it a potentially effective option for oral therapy for MSSA/MRSA infections. It showed superiority to vancomycin for the treatment of MRSA nosocomial pneumonia in the phase 4 ZEPHyR study (NCT00084266).³⁶ It has been proposed as an oral alternative to vancomycin in patients with SAB, but there are few studies available looking at the efficacy of linezolid in this setting. A prospective cohort study of patients with low-risk SAB comparing linezolid (n = 45) and standard IV therapy (n = 90) showed no statistically significant difference was observed in 30-day all-cause mortality. MRSA was only present in 11.1% and 13.3% of patients in the linezolid and standard IV therapy groups, respectively. They excluded complicated SAB, device-related infection, and osteoarticular infections.³⁷

Similarly, in a pooled analysis of 5 RCTs comparing linezolid (given IV for at least 7 days then switch to oral) with vancomycin with SAB, 55% in the linezolid group and 52% in the vancomycin group achieved clinical cure (in intent-to-treat analysis, 38% in linezolid, 36% in vancomycin achieved clinical cure). In those with MRSA bacteremia, clinical cure was achieved in 56% in the linezolid group and 46% in the vancomycin group. The results showed no difference in clinical, microbiological, and survival outcomes between the linezolid and vancomycin groups.³⁸ A recent meta-analysis looked at this pooled analysis along with 2 RCTs, 1 subgroup analysis (1 RCT), and 5 case-control and cohort studies; no difference was seen in primary and secondary effectiveness outcomes between patients treated with linezolid and those treated with vancomycin, teicoplanin, or daptomycin, further supporting a potential role for linezolid as a first-line drug against MRSA bacteremia. Unfortunately, the study had several limitations that may affect its conclusion.³⁹ Linezolid may be a reasonable option as an oral step-down to complete a course of therapy after initial IV treatment for select patients with uncomplicated SAB.

TRIMETHOPRIMSULFAMETHOXAZOLE (TMP-SMX)
TMP-SMX is another antibiotic with excellent oral bioavailability, ranging between 97% and 100% for trimethoprim and 86% and 99% for sulfamethoxazole.⁴⁰ A parallel, open-label RCT (NCT00427076) comparing TMP-SMX and vancomycin for MRSA infections had 252 patients included and only 36% had bacteremia. TMP-SMX did not meet the noninferiority margin compared to vancomycin.⁴¹ The preprint results of the recent international noninferiority phase 3 SABATO trial (NCT01792804) assessed the efficacy and safety of early oral switch therapy in patients at low risk for SAB-related complications after 5 to 7 days of initial IV therapy compared to intravenous standard therapy.

Complicated bacteremia (deep-seated focus, septic shock, persistent bacteremia, and fever), foreign devices, and patients with high risk of SAB complications were excluded. The main source of infection is catheter related (about 65% in each group) and only 7.5% have MRSA bacteremia. TMP-SMX is used in 58.3% of the patients. The primary composite outcome of SAB-related complications within 90 days (relapsing SAB, deep-seated infection, or death attributable to SAB) was not statistically significant between the oral group and the standard intravenous group.⁴² The use of TMP-SMX as initial therapy from SAB has not been fully established, but it may have a role in step-down therapy in very select patients with uncomplicated bacteremia.

CONCLUSION
Presently, only vancomycin and daptomycin have been approved by the FDA for SAB, in particular MRSA bacteremia. However, increasing evidence suggests potential alternatives to these antibiotics. The SABATO trial is awaiting peer review, but its findings are promising. Additionally, high-quality studies with larger sample sizes and higher incidence of MRSA are needed to provide a competitive alternative to vancomycin and daptomycin for the treatment of MRSA bacteremia.

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