Long-term Clinical Safety of Clindamycin and Rifampicin Combination for Hidradenitis Suppurativa

1. Long-term clinical safety of Clindamycin and Rifampicin combination for the treatment of Hidradenitis suppurativa: a critically appraised topic J. Albrecht MD, PhD,1,2 P.A. Baine,3 B. Ladizinski,MD, MPH, MBA.1 G.B. Jemec, MD,4,5 M. Bigby, MD6 1Division of Dermatology, Department of Medicine, J.H. Stroger Hospital of Cook County, Chicago, Illinois, USA 2 Department of Dermatology, Rush Medical College, Chicago, Illinois, USA 3Countway Library of Medicine, Harvard Medical School, Boston, Massachusetts, USA  4 Department of Dermatology, Zealand University Hospital, Roskilde, Denmark. 5 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 6 Department of Dermatology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA  British Journal of Dermatology. DOI: 10.111/bjd.17265

2. Case scenario • 28 year old man with severe occlusion triad for more than 7 years • Failed doxycycline, acitretin, methotrexate, steroid injections, finasteride and dapsone • Unwilling to use prescribed adalumimab • Multiple surgeries, particularly of the face • Never completely controlled • Best results with multiple courses of clindamycin and rifampicin up about half a year • Wishes to continue clindamycin and rifampicin

3. Introduction What’s already known? • Rifampicin for dissecting cellulitis (DS) in one patient in 1988 for 10 weeks • For theoretical reasons clindamycin was added in 1999 for DS treatment • Then both were used for hidradenitis suppurativa (HS) for 10 weeks, which is now the standard length of treatment • Some patients would benefit from maintenance therapy with the clindamycin and rifampicin combination

4. Introduction What’s already known? • Hepatic Cytochrome P450 3A4 Enzyme induction by rifampicin reduces blood levels of clindamycin to sub-therapeutic levels within 2 weeks • Sub-therapeutic levels of clindamycin with rifampicin prevent Staphylococcus resistance to rifampicin • No long-term studies of the combination of clindamycin and rifampicin

5. Approach to Rifampin and Clindamycin • Review of package insert (US), the Summary of Product Characteristics (UK) and the British National Formulary (UK) • Informal survey of providers (9 American dermatologists, 2 British dermatologists and 1 German dermatologist) • Systematic searches as needed, as described below

6. Approach to Rifampin and Clindamycin Rifampin: • Drug Induced Liver Injury • Interstitial nephritis Clindamycin: • Pseudomembranous colitis Based on the conversations with dermatologists the following aspects were added: • Experience with long-term treatment • Drug interactions and enzyme induction (rifampin)

7. Rifampin - Drug induced liver injury • Small increases of liver enzymes that “usually” do not necessitate drug discontinuation or dose adjustment. • Increases bilirubin at beginning of therapy, but sink below normal levels • In other patients, usually with cirrhosis, bilirubin can be elevated without signs of liver injury. • DILI, fatal and symptomatic liver injury reported with jaundice • usually occurs in the first 1-6 weeks, • unlike isoniacide which is later but similar (TB patients)

8. Rifampin – renal failure • Acute renal failure, clinically apparent - interstitial nephritis, • Favorable outcome, if Rifampin is discontinued • Hypersensitivity reaction (type B) • most common with intermittent therapy • or when the drug is resumed after interruption • No evidence of long-term harm

9. Clindamycin and meta-analysis of antibiotic influence on community-acquired Clostridium difficile infection (CA-CDI)

10. Clindamycin and CA-CDI • 2 cases in 800 treated by one dermatologist, no details • 3 meta-analysis addressed CA-CDI • None specified minimum duration of antibiotic therapy • All concluded that prior antibiotic treatment increased the risk of CA-CDI. • Two with odds ratios between 17 and 20. • One MA with two European studies without case of clindamycin associated CDI • Broader meta-analysis identified general AB as most relevant risk factor • but did not estimate risk

11. Long-term combination treatment with clindamycin and rifampicin

12. Drug interactions and enzyme induction (Rifampin) • Rifampin is one of the strongest enzyme inducers known, • ot stereoselective, i.e. it affects (-) and (+) isomers • Enzyme induction vs inhibition • Inhibition: stable after 4-5 half lives of the drug • Induction – 2-3 weeks • Rifampin is faster, begins within 2 days max 9-12 days • Reversal – 2-4 weeks

13. Long-term safety – Clindamycin and Rifampin • Adverse drug events cluster at the beginning of therapy • ICH: The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-life-threatening conditions” • The minimum rifampin therapy for TB US package insert is 6 months • Year therapy is not unusual • We are not aware of specific long-term issues.

14. Long-term safety – Clindamycin and Rifampin • Clindamycin studies for acne for an average of 5 months • Pseudocystiscarinii prophylaxis in very small numbers • Long-term treatment of diabetic feet (no literature) • Long-term use of the drug is relatively rare and thus the data is sparse

15. Conclusion: • The adverse events of clindamycin and rifampicin cluster in the first weeks of treatment. • We could not identify any evidence, or unaddressed concerns that long-term treatment of clindamycin and rifampicin induces significant additional risk over short-term treatment.

16. Case scenario - conclusion • We continued clindamycin and rifampicin • As long as it is tolerated and necessary

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