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 3 Countway 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

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

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

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

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

Approach to Rifampin and Clindamycin 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)

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)

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

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

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

Long-term combination treatment with clindamycin and rifampicin

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 (average 3.35 ± 0.66 hours after 600mg dose, up to 5.08 ± 2.45 hours reported after a 900 mg dose).13 After two days changes in the endoplasmatic reticulum of hepatocytes are noted, but it takes nine to 12 days for the maximum rifampin dose dependent, changes of enzymes to be reached.32 This enzyme induction significantly reduces clindamycin levels in patients treated with the combination of clindamycin and rifampin,30,31 which may explain the paucity of published cases of CA-CDI in the patients with HS. Reversal of the rifampin induced hypermetabolism takes about two to four weeks.35 In summary, the changes occur during the initial 10 week treatment and longer courses add no toxicity.

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. “number of patients treated for 6 months at dosage levels intended for clinical use, should be adequate to characterise the pattern of ADEs over time. To achieve this objective the cohort of exposed subjects should be large enough to observe whether more frequently occurring events increase, or decrease over time as well as to observe delayed events of reasonable frequency (e.g., in the general range of 0.5%-5%). Usually 300-600 patients should be adequate.”18 About 100 patients should be treated for more than 1 year to make a safety assessment.18 Exceptions apply, e.g. when animal models suggest longterm safety concerns.18 Rifampin and clindamycin were introduced in the 1960s. The minimum duration of rifampin therapy for tuberculosis suggested in the US package insert is 6 months,13 and a year therapy is not unusual. We are not aware of longterm issues. For clindamycin the situation is more complicated. Safe use of clindamycin has been reported in small studies for acne for an average of 5 months,28 pseudocystis carinii prophylaxis in very small numbers,29 and longterm treatment of diabetic feet, but longterm use of the drug is relatively rare and thus the data is sparse. However, given the low levels of clindamycin after two weeks of treatments, it is not clear whether this is relevant.30,31

Long-term safety – Clindamycin and Rifampin Clindamycin studies for acne for an average of 5 months Pseudocystis carinii 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 “number of patients treated for 6 months at dosage levels intended for clinical use, should be adequate to characterise the pattern of ADEs over time. To achieve this objective the cohort of exposed subjects should be large enough to observe whether more frequently occurring events increase, or decrease over time as well as to observe delayed events of reasonable frequency (e.g., in the general range of 0.5%-5%). Usually 300-600 patients should be adequate.”18 About 100 patients should be treated for more than 1 year to make a safety assessment.18 Exceptions apply, e.g. when animal models suggest longterm safety concerns.18 Rifampin and clindamycin were introduced in the 1960s. The minimum duration of rifampin therapy for tuberculosis suggested in the US package insert is 6 months,13 and a year therapy is not unusual. We are not aware of longterm issues. For clindamycin the situation is more complicated. Safe use of clindamycin has been reported in small studies for acne for an average of 5 months,28 pseudocystis carinii prophylaxis in very small numbers,29 and longterm treatment of diabetic feet, but longterm use of the drug is relatively rare and thus the data is sparse. However, given the low levels of clindamycin after two weeks of treatments, it is not clear whether this is relevant.30,31

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.

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

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