Renal Readings

Background

Since FDA approval in 2007, eculizamab (anti C5 monoclonal, tradename Soliris) has been used in several disorders stemming from an aberrant complement system. This antibody is approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (atypical HUS). In 2012, three case reports in the New England Journal of Medicine depict successful treatment of membranoproliferative glomerulonephritis (MGPN) with eculizamab (Allison). Other possible uses of this antibody are being investigated.

Eculizumab disrupts the complement systems’ membrane-attack complex, which can increase the risk of invasive disease by Neisseria meningiditis. From a baseline annual US incidence of <1% in adults (Cohn), the reported incidence of meningococcal infection is as high as 3% in adults given eculizamab (Bouts, Hillmen, Dmytrijuk). Pediatric use of eculizamab is likely to result in a much higher incidence of invasive meningococcal disease than just 3%, as the attack rate of N. meningiditis is 3X higher in children compared to adults (Cohn).

Vaccines remain the front-line of protection against invasive infection. The use of meningococcal vaccine is strongly advocated, as noted in the product insert (see link below). The inhibition of parts of the complement complex also confers susceptibility to other encapsulated bacteria (see FDA link below), though likely at a lesser rate than N. meningiditis. Use of available vaccines targeting these bacteria (Streptococcus pneumonia and Haemophilus influenza serotype b) is strongly advocated.

Traditionally, the meningococcal vaccine only covered 4 serotypes (A, C, Y, W135). With the recent approval of the meningococcal serotype B vaccine, the need for antibiotic prophylaxis is now limited to the first 4 weeks following vaccine administration.

If the patient is unwilling or unable to obtain all necessary meningococcal vaccinations prior or during antibody use, antibiotic prophylaxis against N. meningiditis is needed. Criteria for antibiotic selection include ease of administration and coverage against N. meningiditis (with little overlap with Escherichia coli given possible STEC-mediated HUS). Although atypical HUS (by definition) implies the absence of detected STEC, there is the possibility of a false negative results (Gould). STEC-attributed HUS is often diagnosed a week after onset of STEC diarrhea, at a time when the organism may not be detectable (2012 Red Book). It remains prudent to use antibiotic prophylaxis with the narrowest bacterial coverage.

At least one report describes invasive N. gonorrhea disease with use of eculizamab (Gleesing). The authors raise a concern that eculizamab may have increased the morbidity associated with gonococcemia. Coupled with the increasing antimicrobial resistance of N. gonorrhea (CDC 2012), which limits treatment options, medical practitioners should strongly recommend barrier protection and reduction in risky sexual practices for sexually-active patients on eculizamab.

The following are recommendations to mitigate the risk of invasive infections from encapsulated bacteria.

Recipient

• 1. Should be updated on all recommended vaccines for age.

  2. Meningococcal conjugate vaccine (MCV-4, Menactra):

     2. 1. Age 9 months through 23 months:

           1. 1. Primary series of 2 doses, 3 months apart.

              2. Booster in 3 years after completing primary series

              3. Boosters should be repeated every 5 years thereafter

        2. Age 2 years and older (up to 55 years):

           1. 1. Primary series of 2 doses, 2 months apart.

              2. Booster every 5 years

• • 1. Don’t give MCV-4 within 4 weeks of PCV-13, as it may interfere with PCV-13 immune response.

• 1. Meningococcal vaccine (serotype B):

     1. 1. Age 10 years and older:

           1. 1. If Bexsero – two dose series (0 and 1 months)

              2. If Trumenba – three dose series (0, 2, and 6 months)

  2. Pneumococcal vaccination

     1. 1. Conjugate vaccine (PCV-13):

           1. 1. Age 6-18 years: single supplemental dose of PCV-13 should be given

        2. Polysaccharide vaccine (PPSV23):

           1. 1. Age 2 years and older:

                 2. 1. Finish PCV-13 dosing first (if primary or supplemental)

                    2. Given 8 weeks after last dose of PCV-13

                    3. Give 2^nd dose of PPSV23 in 5 years after first dose.

                       1. No more than 2 doses of PPSV23

• 1. Haemophilus influenzae serotype B (Hib) vaccination.

     1. 1. Age 12-59 months:

           1. 1. Unimmunized or only 1 Hib before 12 months of age: give 2 doses (separate by 2 months)

              2. If only received 2 doses before 12 months of age: give one additional dose

        2. Age >59 months:

           1. 1. If unimmunized: give 1 dose of Hib vaccine

  2. Annual influenza vaccine (inactivated)

     1. 1. This reduces the risk of secondary bacterial infections

• 1. Antibiotic prophylaxis (against N. meningitides)

     1. 1. To be continued until 4 weeks after completion of meningococcal vaccine series

           1. 1. Lifelong prophylaxis may be considered if not able to obtain vaccine coverage for all 5 serotypes

        2. Azithromycin

           1. 1. 2.5 mg/k/day (up to max of 125 mg) given daily.

        3. Penicillin G benzathine (bicillin) – if compliance is issue

           1. 1. Wt <27 kg: 600,000 Units IM every 4 weeks

              2. Wt >=27 kg: 1.2 million Units IM every 4 weeks

        4. Amoxicillin may be alternative medication if STEC-HUS is conclusively discounted

           1. 1. 20 mg/k/day (up to max of 250 mg) given daily.

              2. If STEC-HUS is not ruled out, would use azithromycin or IM PenG as antimicrobial prophylaxis until 4 weeks past 1^st eculizamab. Then can use amoxicillin.

• • 1. Oral penicillin (PenV) is NOT an option, as MIC against N. meningitidis is higher than parenteral penicillin (PenG) (Backmann)

• 1. Prevention against Neisseria gonorrheae

     1. 1. Condom use in sexually active patients

Household contacts

• 1. Strong recommendation for all to be current on routine and recommended vaccinations for age.

     1. 1. Particularly contacts between 11-18 years should have recommended meningococcal vaccines

  2. Annual influenza vaccine (inactivated)

     1. 1. This reduces the risk of secondary bacterial infections

References

Allison SJ. Glomerular disease: Eculizumab for the treatment of MPGN. Nat Rev Nephrol 2012;8:314.

American Academy of Pediatrics. Pickering LK, Baker CJ, Kimberlin DW, Long SS eds. Red Book 2012: Report of the Committee on Infectious Diseases, 29^th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2012.

Backmann A et al. Plasmid carriage and antibiotic susceptibility of Neisseria meningitidis strains isolated in Sweden 1981-1990. Eur J Clin Microbiol Infect Dis 1993;12:683-9.

Bouts A et al. Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy. Pediatr Nephrol 2011;26:1919-20.

Centers for Disease Control and Prevention (CDC). Update to CDC’s Sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep 2012;61:590-4.

Centers for Disease Control and Prevention (CDC) Prevention and Control of Meningococcal Disease - Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2013;62(No. RR-2):1-28.

Cohn AC et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clin Infect Dis 2010;50:184-91.

Gleesing J et al. Gonococcal septic shock associated with eculizumab treatment. Pediatr Infect Dis J 2012: 31:543.

Gould LH et al. Recommendations for diagnosis of Shiga toxin-producing Escherichia coli infections by clinical laboratories. MMWR Recomm Rep 2009;58(RR-12):1-14.

Hillmen P et al. Long-term effect of the complement inhibitor eculizamab on kidney function in patients with paroxysmal nocturnal hemoglobulinuria. Am J Hematol 2010; 85:553-9.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125166s172lbl.pdf (product insert)

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm273089.htm (FDA report)

Rubin LG et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014 Feb;58:309-18.