Pharmacology Consult

Preventing meningococcal disease in patients receiving Soliris

Soliris is a humanized monoclonal antibody that has emerged as a life-saving therapy for certain rare diseases but carries with it the risk for bacterial infections, particularly from Neisseria species. As such, vaccination against N. meningitidis and other encapsulated bacteria — like Streptococcus pneumoniae and Haemophilus influenzae — has long been recommended for people taking the drug. More recently, breakthrough meningococcal infections in appropriately immunized patients have prompted discussions of whether additional long-term antibiotic prophylaxis is needed.

Eculizumab: Indications, mechanisms and risks

Soliris (eculizumab, Alexion Pharmaceuticals) is the primary treatment for patients with paroxysmal nocturnal hemoglobinuria, for which it gained initial FDA approval in 2007. Since then, eculizumab has been approved to treat atypical hemolytic uremic syndrome (2011) and certain types of generalized myasthenia gravis (2017). Eculizumab has also been investigated in the settings of transplanted organ rejection and thrombotic microangiopathy (TMA) in bone marrow and solid organ transplant recipients. The duration of eculizumab treatment may vary according to disease state and patient characteristics and may be continued as lifelong therapy.

Leah Molloy

These disease states are all secondary to dysfunction of the complement part of the immune system. Blockade of the complement system prevents the life-threatening complications of uncontrolled complement activation and its activity against mislabeled healthy targets. Eculizumab binds to complement protein C5 to block cleavage into C5a and C5b. C5a is a mediator of inflammation and thrombosis, and C5b, in combination with other complement proteins, forms the membrane attack complex (MAC) that drives hemolysis in addition to inflammation and thrombosis.

Although MAC inhibition is desirable to prevent hemolysis, this complex is needed for serum bactericidal activity (SBA), which is part of the body’s innate defense against infection and one of two pathways by which the human body may kill N. meningitidis. The second pathway is opsonophagocytosis (OPA) — phagocytosis of cells targeted by immunization. The elimination of the first pathway and the reliance of the second on immunization present a clear need to vaccinate people taking eculizumab. For these reasons, previously unimmunized patients should receive meningococcal vaccination at least 2 weeks before starting eculizumab. Unimmunized patients who require urgent eculizumab therapy should be vaccinated as soon as possible. Although no specific agents are recommended, the eculizumab package insert notes that most patients in this situation received prophylactic antibiotics until at least 2 weeks after vaccination. To minimize these risks and ensure awareness and preventive strategies, only prescribers enrolled in the Risk Evaluation and Mitigation Strategy (REMS) program may obtain eculizumab. Patients should additionally remain up to date with all vaccinations.

Breakthrough meningococcal infections: Characteristics and implications

In a July 2017 MMWR, the CDC reported 16 cases of meningococcal disease in patients taking eculizumab, 14 of whom had been appropriately vaccinated. Two key observations were discussed at the June 2017 meeting of th-e CDC Advisory Committee of Immunization Practices (ACIP). First, at least half of the cases were caused by nongroupable (NG) strains of N. meningitidis — a typically nonpathogenic strain commonly found in patients with asymptomatic nasopharyngeal carriage. The two currently available meningococcal vaccine types are the quadrivalent vaccine, targeted against serogroups A, C, W and Y; and the serogroup B vaccines, which are approved for patients aged 10 years and older. The quadrivalent vaccines confer no activity against NG strains. Although some cross-activity may exist between the serogroup B vaccine and NG strains, this has not been assessed and the serogroup B vaccine cannot be considered reliable protection against NG strains at this time.

The second observation reviewed at the ACIP meeting was in vitro whole blood killing of N. meningitidis. Blood from an immunized donor was effective at killing serogroups B and C and NG N. meningitidis. However, when retested in the presence of eculizumab, the bacteria were not killed and instead were able to replicate. Knowing that SBA is inhibited by eculizumab, these findings suggest that OPA is also impaired, either directly or owing to the absence of SBA.

Taken together, these observations indicate that vaccination alone may be unreliable to prevent meningococcal infection in patients taking eculizumab and suggest a potential role for antibiotic prophylaxis. Questions raised at the ACIP meeting included which drugs may be preferred, and whether certain patient populations should be selected for prophylaxis. Potential criteria for prophylaxis might account for age as a risk factor, either to predict the likelihood of asymptomatic carriage or the risk of disease. Clinicians may also consider the status of the immune system and the anticipated duration of eculizumab therapy.

Antibiotic prophylaxis: Clinical considerations for risk reduction

In their 2018 consensus document, the European Society of Clinical Microbiology and Infectious Diseases recommended prophylactic antibiotics for 4 weeks following meningococcal vaccination and advises prescribers to strongly consider continuing prophylaxis for the full duration of eculizumab therapy for previously immunocompromised patients. Guidelines from France and the United Kingdom require prolonged antibiotic prophylaxis for all patients during eculizumab treatment. In the absence of formal recommendations in the United States, some institutions have developed their own practice guidelines. For example, a 2015 Children’s Hospital of Philadelphia case study includes a recommendation for indefinite antibiotic prophylaxis throughout the duration of eculizumab treatment for children. A 2016 report from Cincinnati Children’s Hospital Medical Center described patients receiving eculizumab for TMA after bone marrow transplant who were unable to receive meningococcal vaccination because of severe immunosuppression. Instead of vaccination, these patients received prophylactic antibiotics throughout eculizumab treatment and until 8 weeks after completion, or until complement recovery. No breakthrough meningococcal infections occurred.

Available guidance documents reference a variety of antibiotics to protect against meningococcal disease in patients taking eculizumab, including penicillin, ciprofloxacin and erythromycin. Antibiotic susceptibility testing was performed on the N. meningitidis isolates from 14 of the 16 breakthrough cases described in the MMWR. Of these, 10 strains were fully susceptible to penicillin, three were intermediately susceptible and one was resistant. All strains were susceptible to both ceftriaxone and azithromycin, and 13 of the 14 strains were susceptible to ciprofloxacin. Similarly, a 2015 report from the Active Bacterial Core Surveillance team of the CDC’s Emerging Infections Program identified uniform susceptibility of N. meningitidis to ceftriaxone and azithromycin and about 10% intermediate susceptibility to penicillin G.

Penicillin is commonly used for long-term pneumococcal prophylaxis in patients with past rheumatic fever or children with functional or anatomical asplenia, and available guidelines suggest the same dosing for patients receiving eculizumab. Erythromycin is recommended as a potential alternative for patients with penicillin allergies, and at the same doses. Some guidelines recommend initiating prophylaxis with 2 weeks of ciprofloxacin before de-escalating to penicillin. Clinicians may consider initial administration of ceftriaxone or ciprofloxacin to eradicate potential nasopharyngeal carriage before penicillin prophylaxis. The table lists potential options for antibiotic prophylaxis. Although azithromycin remains highly active against N. meningitidis strains evaluated from both the previously described breakthrough infections and from susceptibility surveillance testing, data are insufficient to recommend a prophylactic dose. As with all medications, these antibiotics are not without side effects, and patients and families must be counseled, particularly for drug interactions and QT prolongation with macrolides. Avoidance of chronic fluoroquinolone exposure is desirable in any population but should be particularly avoided in children.

Depending on the indication, eculizumab may be initiated in critically ill patients already receiving broad-spectrum antibiotics that are active against N. meningitidis, negating the need for additional prophylaxis in the acute setting. Because no prophylactic regimen can ensure uniform protection, patients and families must be educated to recognize signs and symptoms of potential meningococcal infection. All health care providers involved in the care of these patients must maintain a high index of suspicion and take even mild or nonspecific signs of illness seriously.

Disclosure: Molloy reports no relevant financial disclosures.

Soliris is a humanized monoclonal antibody that has emerged as a life-saving therapy for certain rare diseases but carries with it the risk for bacterial infections, particularly from Neisseria species. As such, vaccination against N. meningitidis and other encapsulated bacteria — like Streptococcus pneumoniae and Haemophilus influenzae — has long been recommended for people taking the drug. More recently, breakthrough meningococcal infections in appropriately immunized patients have prompted discussions of whether additional long-term antibiotic prophylaxis is needed.

Eculizumab: Indications, mechanisms and risks

Soliris (eculizumab, Alexion Pharmaceuticals) is the primary treatment for patients with paroxysmal nocturnal hemoglobinuria, for which it gained initial FDA approval in 2007. Since then, eculizumab has been approved to treat atypical hemolytic uremic syndrome (2011) and certain types of generalized myasthenia gravis (2017). Eculizumab has also been investigated in the settings of transplanted organ rejection and thrombotic microangiopathy (TMA) in bone marrow and solid organ transplant recipients. The duration of eculizumab treatment may vary according to disease state and patient characteristics and may be continued as lifelong therapy.

Leah Molloy

These disease states are all secondary to dysfunction of the complement part of the immune system. Blockade of the complement system prevents the life-threatening complications of uncontrolled complement activation and its activity against mislabeled healthy targets. Eculizumab binds to complement protein C5 to block cleavage into C5a and C5b. C5a is a mediator of inflammation and thrombosis, and C5b, in combination with other complement proteins, forms the membrane attack complex (MAC) that drives hemolysis in addition to inflammation and thrombosis.

Although MAC inhibition is desirable to prevent hemolysis, this complex is needed for serum bactericidal activity (SBA), which is part of the body’s innate defense against infection and one of two pathways by which the human body may kill N. meningitidis. The second pathway is opsonophagocytosis (OPA) — phagocytosis of cells targeted by immunization. The elimination of the first pathway and the reliance of the second on immunization present a clear need to vaccinate people taking eculizumab. For these reasons, previously unimmunized patients should receive meningococcal vaccination at least 2 weeks before starting eculizumab. Unimmunized patients who require urgent eculizumab therapy should be vaccinated as soon as possible. Although no specific agents are recommended, the eculizumab package insert notes that most patients in this situation received prophylactic antibiotics until at least 2 weeks after vaccination. To minimize these risks and ensure awareness and preventive strategies, only prescribers enrolled in the Risk Evaluation and Mitigation Strategy (REMS) program may obtain eculizumab. Patients should additionally remain up to date with all vaccinations.

PAGE BREAK

Breakthrough meningococcal infections: Characteristics and implications

In a July 2017 MMWR, the CDC reported 16 cases of meningococcal disease in patients taking eculizumab, 14 of whom had been appropriately vaccinated. Two key observations were discussed at the June 2017 meeting of th-e CDC Advisory Committee of Immunization Practices (ACIP). First, at least half of the cases were caused by nongroupable (NG) strains of N. meningitidis — a typically nonpathogenic strain commonly found in patients with asymptomatic nasopharyngeal carriage. The two currently available meningococcal vaccine types are the quadrivalent vaccine, targeted against serogroups A, C, W and Y; and the serogroup B vaccines, which are approved for patients aged 10 years and older. The quadrivalent vaccines confer no activity against NG strains. Although some cross-activity may exist between the serogroup B vaccine and NG strains, this has not been assessed and the serogroup B vaccine cannot be considered reliable protection against NG strains at this time.

The second observation reviewed at the ACIP meeting was in vitro whole blood killing of N. meningitidis. Blood from an immunized donor was effective at killing serogroups B and C and NG N. meningitidis. However, when retested in the presence of eculizumab, the bacteria were not killed and instead were able to replicate. Knowing that SBA is inhibited by eculizumab, these findings suggest that OPA is also impaired, either directly or owing to the absence of SBA.

Taken together, these observations indicate that vaccination alone may be unreliable to prevent meningococcal infection in patients taking eculizumab and suggest a potential role for antibiotic prophylaxis. Questions raised at the ACIP meeting included which drugs may be preferred, and whether certain patient populations should be selected for prophylaxis. Potential criteria for prophylaxis might account for age as a risk factor, either to predict the likelihood of asymptomatic carriage or the risk of disease. Clinicians may also consider the status of the immune system and the anticipated duration of eculizumab therapy.

Antibiotic prophylaxis: Clinical considerations for risk reduction

In their 2018 consensus document, the European Society of Clinical Microbiology and Infectious Diseases recommended prophylactic antibiotics for 4 weeks following meningococcal vaccination and advises prescribers to strongly consider continuing prophylaxis for the full duration of eculizumab therapy for previously immunocompromised patients. Guidelines from France and the United Kingdom require prolonged antibiotic prophylaxis for all patients during eculizumab treatment. In the absence of formal recommendations in the United States, some institutions have developed their own practice guidelines. For example, a 2015 Children’s Hospital of Philadelphia case study includes a recommendation for indefinite antibiotic prophylaxis throughout the duration of eculizumab treatment for children. A 2016 report from Cincinnati Children’s Hospital Medical Center described patients receiving eculizumab for TMA after bone marrow transplant who were unable to receive meningococcal vaccination because of severe immunosuppression. Instead of vaccination, these patients received prophylactic antibiotics throughout eculizumab treatment and until 8 weeks after completion, or until complement recovery. No breakthrough meningococcal infections occurred.

PAGE BREAK

Available guidance documents reference a variety of antibiotics to protect against meningococcal disease in patients taking eculizumab, including penicillin, ciprofloxacin and erythromycin. Antibiotic susceptibility testing was performed on the N. meningitidis isolates from 14 of the 16 breakthrough cases described in the MMWR. Of these, 10 strains were fully susceptible to penicillin, three were intermediately susceptible and one was resistant. All strains were susceptible to both ceftriaxone and azithromycin, and 13 of the 14 strains were susceptible to ciprofloxacin. Similarly, a 2015 report from the Active Bacterial Core Surveillance team of the CDC’s Emerging Infections Program identified uniform susceptibility of N. meningitidis to ceftriaxone and azithromycin and about 10% intermediate susceptibility to penicillin G.

Penicillin is commonly used for long-term pneumococcal prophylaxis in patients with past rheumatic fever or children with functional or anatomical asplenia, and available guidelines suggest the same dosing for patients receiving eculizumab. Erythromycin is recommended as a potential alternative for patients with penicillin allergies, and at the same doses. Some guidelines recommend initiating prophylaxis with 2 weeks of ciprofloxacin before de-escalating to penicillin. Clinicians may consider initial administration of ceftriaxone or ciprofloxacin to eradicate potential nasopharyngeal carriage before penicillin prophylaxis. The table lists potential options for antibiotic prophylaxis. Although azithromycin remains highly active against N. meningitidis strains evaluated from both the previously described breakthrough infections and from susceptibility surveillance testing, data are insufficient to recommend a prophylactic dose. As with all medications, these antibiotics are not without side effects, and patients and families must be counseled, particularly for drug interactions and QT prolongation with macrolides. Avoidance of chronic fluoroquinolone exposure is desirable in any population but should be particularly avoided in children.

Depending on the indication, eculizumab may be initiated in critically ill patients already receiving broad-spectrum antibiotics that are active against N. meningitidis, negating the need for additional prophylaxis in the acute setting. Because no prophylactic regimen can ensure uniform protection, patients and families must be educated to recognize signs and symptoms of potential meningococcal infection. All health care providers involved in the care of these patients must maintain a high index of suspicion and take even mild or nonspecific signs of illness seriously.

Disclosure: Molloy reports no relevant financial disclosures.