Katie E. Barber, PharmD*

Interleukin-6 (IL-6) is a cytokine responsible for organ development, inflammation, and immune responses.

 As a key stimulator of acute phase proteins, IL-6 is associated with proinflammatory responses, particularly when dysregulated or continually synthesized.

 Exaggerated synthesis of IL-6 in the lungs, secondary to the presence of the nucleocapsid protein of severe acute respiratory syndrome coronavirus 2, has been linked to cytokine release syndrome (CRS) in critically ill 

 patients; this subsequently led to exploration of IL-6 inhibitor use.

 Three recombinant monoclonal antibodies (mABs) targeted against IL-6 have been explored in the treatment of COVID-19 patients with suspected CRS: tocilizumab (TOCI), sarilumab (SARI), and siltuximab (SILT). TOCI was the first IL-6 inhibitor developed, with subsequent IL-6 inhibitors targeting the IL-6 pathway through different target sites or receptor/cytokine binding affinity.

In general, IL-6 inhibitors prevent human IL-6 from binding to IL-6 receptors, thus impeding the formation of immune signaling complexes on cell surfaces. Differences exist in drug target and binding affinity for human IL-6, but it is unclear how these impact COVID-19 treatment. Specifically, TOCI is a humanized mAB that binds to soluble and membrane-bound IL-6 receptors, whereas SARI is a fully human anti—IL-6 receptor mAb.

 SILT is a chimeric, human—murine mAB that binds to and neutralizes the human IL-6 cytokine itself.

 There are no known differences in efficacy among these agents for their labeled indications or in COVID-19 infections.

Few data describe the pharmacokinetics of IL-6 inhibitors, which can vary from linear (TOCI, SILT) to Michaelis—Menten (SARI).

 The half-life of these agents can range from 8 to 30 days, with no noted dose adjustments for renal or hepatic disease; however, safety data in specialized populations are limited.

 Most toxicities of IL-6 inhibitor use have been observed with long-term use and include neutropenia, thrombocytopenia, elevated liver enzymes, rash, and pruritis. However, neutropenia and thrombocytopenia have been reported with short-term IL-6 inhibitor use in COVID-19 patients, and caution should be exercised in patients with low neutrophil or platelet counts.

Data surrounding the use of IL-6 inhibitors to treat COVID-19 infections are still emerging, and currently available evidence includes case reports, case series, and nonrandomized trials with and without control groups

The use of TOCI in 9 patients with COVID-19 pneumonia or respiratory failure were documented in 6 case reports.

 Patient age ranged from 40 to 71 years, and 6/9 (66.7%) patients were male. TOCI administration occurred after worsening chest imaging or shortness of breath in 8 of 9 patients. Three patients received monotherapy with TOCI, while 6 received concomitant lopinavir—ritonavir (L/r), hydroxychloroquine (HCQ) + azithromycin (AZM), or HCQ + L/r. No adverse drug reactions (ADRs) occurred. Two of the 9 patients expired.

A TOCI case series by Luo et al examined 15 COVID-19—positive patients whose median age was 73 years: 2 (13.3%) were moderately ill, 6 (40%) severely ill, and 7 (46.7%) critically ill.

 All patients received a single dose of TOCI (80-600 mg), while 5 (33%) received 2 to 3 doses. Eight (53%) patients received concomitant methylprednisolone. Nine (60%) patients were stabilized post TOCI therapy, 2 (13.3%) experienced worsened COVID-19 symptoms, and 3 (20%) patients expired.

A TOCI case series by Xu et al included 21 patients with either severe (81%) or critical (19%) COVID-19 infection.

 The average age was 57 years, and 18 (86%) patients were male. All included patients had abnormal chest CT imaging documenting ground glass opacities or bilateral infiltrates. Eighteen (86%) patients received 1 dose of TOCI, while 3 (14%) patients received 2 doses. All patients had dyspnea, fever, and elevated C-reactive protein (CRP), IL-6, and white blood cells. Within 24 hours, all patients experienced defervescence, and within 5 days, 15 (71%) had reduced oxygen requirements. No patients experienced any ADRs.

A SILT case series included 21 COVID-19 patients with acute respiratory distress syndrome requiring noninvasive ventilation (NIV).

 The median age was 64 years, and all patients received the standard of care (SOC) combined with SILT 11 mg/kg/day. Five (24%) patients received a second dose. Eighteen (86%) received SILT within 24 hours of NIV. Improvement in symptoms occurred in 7 (33%) patients, 9 (43%) patients stabilized, and 5 (24%) had worsening symptoms resulting in intubation or death.

A study by Sciascia et al included 63 patients with a mean age of 63 years who received a single dose of TOCI at either 8 mg/kg intravenously (IV) or 324 mg subcutaneously.

 Administration of the drug within 6 days of admission was associated with a 2-fold increased likelihood of survival and an increase in partial pressure of arterial oxygen/fraction of inspired oxygen ratio by day 14. Toniati et al examined 100 patients with severe COVID-19 pneumonia requiring mechanical ventilation (MV).

 The median age was 62 years, and 88 (88%) patients were male. Eighty-seven (87%) patients received 2 doses of TOCI at 8 mg/kg (maximum, 800 mg) given 12 hours apart, and 13 (13%) patients received a third dose 24 hours later. Within 72 hours of TOCI administration, 58 had improvement in respiratory symptoms, while 5 worsened. At 10 days post TOCI, 77 had improved respiratory function, 23 had worsening function, and 20/23 (87%) had died. Three patients experienced ADRs (2, septic shock and death; 1, gastrointestinal perforation).

A phase 2 study was conducted comparing SARI 400 mg vs 200 mg vs placebo in 457 patients with COVID-19 infection.

 The patients were classified as having either severe illness (28%), critical illness (49%), or multisystem organ dysfunction (23%). Preliminary analysis demonstrated that SARI rapidly lowered CRP with no ADRs observed. Approximately 365 (80%) patients were discharged alive, 45 (10%) died, and 45 (10%) remained hospitalized at the interim analysis.

Another comparator study examined the composite end point of intensive care unit (ICU) admission and/or mortality in 45 COVID-19 patients who received either 1 or 2 doses of TOCI or SOC (HCQ or L/r + antibiotics +/— corticosteroids).

 Patients in the TOCI group were more likely to be 70 years or older and had higher Charlson Comorbidity Index scores, oxygen requirements, and greater lymphopenia and CRP than patients in the SOC group. However, patients in the TOCI group had lower rates of MV and ICU admission and/or death (72% vs 25%).

Roumier et al matched TOCI patients to SOC patients based on age, gender, and disease severity.

 Sixty included patients (30 [50%] TOCI, 30 [50%] SOC) were less than 80 years of age and had severe, rapidly deteriorating pneumonia, high CRP, and at least 5 days of COVID-19 infection. Their median age was 50 years, and 48 (80%) were male. Patients were given 1 to 2 doses of IV TOCI 8 mg/kg. Two (6.7%) TOCI patients also received HCQ and AZM, and 2 (6.7%) control patients received high-dose methylprednisolone. After 8 days, TOCI reduced the requirement for MV (weighted odds ratio [OR], 0.42; 95% CI, 0.20-0.89), and TOCI patients were more likely to avoid ICU admission (weighted OR, 0.17; 95% CI, 0.06-0.48). Three (10%) TOCI patients experienced ADRs: mild hepatic cytolysis (2/30, 6.7%) and ventilator-associated pneumonia (1/30, 3.3%).

When examining all currently available data, it appears that IL-6 inhibitors have the potential to be used in those COVID-19 patients who have extensive lung involvement and elevated IL-6 concentrations. Care should be taken to watch for the development of neutropenia, thrombocytopenia, and liver injury. Additionally, optimal timing of IL-6 inhibitor initiation is unknown, as symptoms can worsen in some patients after administration. Results from randomized controlled trials can shed light on what the true place in therapy is for IL-6 inhibitors in the fight against COVID-19.

Wagner is a clinical assistant professor at the University of Mississippi School of Pharmacy with a practice site at the University of Mississippi Medical Center. She currently serves as the chair of the SIDP Antimicrobial Stewardship Committee and as a committee member for the ACCP ID PRN Research Committee. 

Veve is a clinical assistant professor at the University of Tennessee College of Pharmacy. He maintains practice as an infectious diseases clinical pharmacist at the University of Tennessee Medical Center. 

Barber is an assistant professor at the University of Mississippi School of Pharmacy and a clinical specialist in infectious diseases at the University of Mississippi Medical Center.

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Articles

Use of an IL-6 inhibitor has the potential to prevent the cytokine storm caused by severe COVID-19 infection.

Using IL-6 Inhibitors to Treat COVID-19

(MRSA) is a common community and nosocomial pathogen capable of causing a wide variety of infections. Mortality rates associated with MRSA bacteremia have been reported as high as 50%. Despite the prevalence of MRSA, significant controversy exists regarding optimal treatment strategies, particularly for patients with complicated and/or persistent infections. Vancomycin remains an impressive workhorse in the MRSA treatment landscape; however, its utility is limited by slow bactericidal activity, evolving dosing strategies that necessitate labor-intensive therapeutic drug monitoring, nephrotoxicity, and suboptimal clinical outcomes data despite decades of use. Daptomycin is an alternative first-line agent for the treatment of MRSA bacteremia and is associated with less nephrotoxicity and more convenient dosing strategies compared with vancomycin. Nonetheless, the outcomes of patients treated with standard daptomycin doses are underwhelming, as only 44% of patients with MRSA bacteremia achieved clinical success following receipt of a 6-mg/kg daily dose.

 Of concern, gene mutations that confer daptomycin tolerance and enhanced 

 Unlike treatment with vancomycin, higher doses of daptomycin (ie, ≥8 mg/kg/day) demonstrate more rapid in vitro killing and suppression of resistance and are associated with improved clinical outcomes.

An alternative approach is combination therapy with a β-lactam, which offers similar advantages as high-dose daptomycin but may allow for use of lower vancomycin or daptomycin doses.

 Historically, combination approaches have been employed for treatment refractory or persistent MRSA bacteremia; however, new data indicate that such approaches could have benefit if employed much earlier.

The Infectious Diseases Society of America clinical practice guidelines for the treatment of MRSA infections recommend high-dose daptomycin (ie, 10 mg/kg/day) in combination with another antibiotic as salvage therapy for persistent MRSA bacteremia and/or vancomycin treatment failures.

 Unfortunately, there are minimal data to demonstrate which antibiotic combinations are preferred or when combination therapy should be initiated or stopped. Moreover, the role of novel MRSA-active antibiotics is not represented, as the guidelines were published only months after ceftaroline received approval from the US Food and Drug Administration and years before even newer agents were introduced on the market. Interestingly, patients often receive empiric “combination therapy” in clinical practice with vancomycin plus either cefepime or piperacillintazobactam. Recent data suggest that patients receiving at least 24 hours of cefepime have improved clearance of MRSA bloodstream infections compared with patients receiving vancomycin monotherapy, and this may be a preferred empiric regimen if cefepime has adequate in vitro activity against gram-negative nosocomial pathogens within the institution.

β-Lactam antibiotics are likely the preferred partner agents for vancomycin and daptomycin because of their enhanced safety compared with other antibiotic classes that may be considered for synergy and because of the favorable economic profile of older β-lactam agents such as cefazolin. The absence of real-world clinical data for the use of novel MRSA-active agents for complicated infections, taken with compelling in vitro synergy data and desire to use antibiotics judiciously, warrants the investigation of β-lactam combination therapies. Briefly, we review the available in vitro and clinical data for β-lactam combination therapies in the treatment of MRSA bacteremia.

Several mechanisms of synergy exist between β-lactams and vancomycin or daptomycin. Notably, increasing glyco- and lipopeptide resistance is associated with improved susceptibility to β-lactam antibiotics through a phenomenon called the seesaw effect. Possible explanations include increased expression of penicillin-binding protein (PBP) 2, decreased PBP4, and/ or inactivation of the 

, PBP1 blockade is most strongly associated with daptomycin potentiation. Therefore, β-lactams with affinity for PBP1 (eg, cefazolin, nafcillin, meropenem) enhance anti-MRSA activity of daptomycin, whereas those with minimal affinity (eg, ceftriaxone, cefoxitin) do not.

 Interestingly, ceftaroline is more active against MRSA isolates with higher vancomycin and daptomycin minimum inhibitory concentrations because of enhanced PBP2 binding.

 Other bacterial genetic and metabolic adaptions may confer changes to the bacterial cell wall. Indeed, ceftaroline enhances daptomycin-induced cell membrane depolarization and reduces cell wall thickness of both daptomycin-susceptible and -nonsusceptible strains of 

 This potent synergy may result in clinical de-escalation or sparing of higher daptomycin doses.

Synergy may also be explained by immune system regulation. Sakoulas and colleagues found that exposure to nafcillin significantly increased the activity of host defense peptides, particularly human cathelicidin LL-37, against 

 The effect was more pronounced at higher doses; however, synergistic effects were observed at extremely low nafcillin concentrations. Importantly, the effect was also observed with ampicillin, piperacillin, cefazolin, ceftriaxone, and ceftaroline. The combinations of vancomycin and cefazolin, cefepime, ceftaroline, and nafcillin all demonstrated improved in vitro killing against vancomycin-susceptible, heterogeneous VISA, as well as VISA strains, compared with vancomycin alone.

Retrospective analyses of patients receiving vancomycin or daptomycin plus a β-lactam show shorter durations of bacteremia but no impact on rates of clinical failure compared with monotherapy.

 Notably, however, bacteremia persisted for a median of 10 days prior to combination therapy initiation in these studies.

 Indeed, ceftaroline has been used successfully with vancomycin and daptomycin as salvage therapy for patients with refractory, persistent MRSA bacteremia.

 Ceftaroline is an attractive choice to use in combination because it is the only β-lactam with in vitro activity against MRSA in addition to the synergistic laboratory effects previously described. The question of whether ceftaroline monotherapy would demonstrate improved clinical outcomes compared with vancomycin or daptomycin monotherapy or combination regimens remains unanswered. Patients are more likely to benefit from combination therapy earlier in the treatment course, particularly patients at higher risk of mortality.

 A retrospective evaluation of 171 patients with MRSA bacteremia found mortality was reduced by 80% at 60 days for patients with a primary endovascular source receiving combination therapy with daptomycin plus ceftaroline within 72 hours of index blood culture.

 In a recent prospective trial, patients with MRSA bacteremia were randomized to daptomycin (6-8 mg/kg/day) plus ceftaroline (600 mg every 8 hours) or standard monotherapy within 72 hours.

 No patients (0 of 17) in the combination therapy arm died compared with 26% (6 of 23) of patients in the standard therapy arm, resulting in early termination of the study. All deaths were among patients with an endovascular source, and the majority (5 of 6) had serum IL-10 concentrations >5 pg/mL. The median duration of combination therapy was 8 days before de-escalation to monotherapy, which is notable because evidence to support the duration of combination therapy is lacking. Short durations of early combination followed by definitive monotherapy may be economically advantageous and spare unnecessary antibiotic exposures and toxicities.

An earlier prospective clinical trial that evaluated β-lactam combination therapy for MRSA bacteremia enrolled 60 patients who were randomly assigned to receive vancomycin or vancomycin plus flucloxacillin for 7 days within 48 hours of the first positive blood culture.

Patients receiving combination therapy had a 24-hour shorter duration of bacteremia, and fewer patients experienced persistent bacteremia. No difference in mortality was observed, owing to the small sample size. A subsequent openlabel trial (NCT02365493) of adult patients with MRSA bacteremia was designed to further elucidate the clinical effectiveness of early combination therapy based on these data. Patients were randomized within 72 hours of the first positive blood culture to either standard therapy (vancomycin or daptomycin monotherapy) or combination therapy with vancomycin or daptomycin plus 7 days of an antistaphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin).

 The primary outcome is a composite measure of all-cause mortality, persistent bacteremia at 5 days or greater, microbiological relapse (defined as a MRSA-positive blood culture at least 72 hours after a negative culture), and microbiological treatment failure (defined as MRSA isolated from any sterile site except urine at least 14 days after randomization). The trial closed enrollment in December 2018 per recommendations of the data safety monitoring committee, and the infectious disease community eagerly awaits results.

Based on available and emerging data, it is reasonable to employ combination therapy with a PBP1-active β-lactam or ceftaroline early in the MRSA bacteremia treatment course, particularly in patients at the highest risk of treatment failure or death. Seven days of combination therapy may be sufficient if employed early in the treatment course, but more clinical data are needed to determine the optimal drug pairings and duration of combination therapy. Empiric monotherapy with ceftaroline compared with vancomycin or daptomycin monotherapy or combination regimens needs to be explored.

McCreary serves as an antimicrobial stewardship/ infectious diseases clinical pharmacist at the University of Pittsburgh Medical Center in Pennsylvania. *She is a member of the Society of Infectious Diseases Pharmacists.

Barber is an assistant professor at the University of Mississippi School of Pharmacy and a clinical specialist in infectious diseases at the University of Mississippi Medical Center. *She is a member of the Society of Infectious Diseases Pharmacists.

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