Efficacy of Rifampin-Moxifloxacin-Metronidazole Combination Therapy in Hidradenitis Suppurativa

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Original Paper

Dermatology DOI: 10.1159/000321716

Efficacy of Rifampin-Moxifloxacin-Metronidazole Combination Therapyin Hidradenitis Suppurativa

Olivier Join-Lambert a, b, j, k Hélène Coignard a, c, k Jean-Philippe Jais a, d Hélène Guet-Revillet a, b, j, k Sylvain Poirée a, e Sylvie Fraitag a, f Vincent Jullien a, g Florence Ribadeau-Dumas h, k Jacques Thèze h, k Anne-Sophie Le Guern h, k Sylvie Behillil h, k Anne Leflèche i Patrick Berche a, b, k Paul Henri Consigny h, k Olivier Lortholary a, c, k Xavier Nassif a, b, j, k Aude Nassif h, k

a Université Paris Descartes, Faculté de Médecine Paris Descartes, b Laboratoire de Microbiologie, c Service des Maladies Infectieuses et Tropicales, d Service d’Informatique Médicale et de Biostatistiques, e Service de Radiologie Adulte, f Service d’Anatomie et de Cytologie Pathologiques, Hôpital Necker-Enfants malades, Assistance-Publique-Hôpitaux de Paris, g Service de Pharmacologie Saint-Vincent-de-Paul, Assistance-Publique-Hôpitaux de Paris, h Centre Médical, i Cellule d’Intervention Biologique d’Urgence Institut Pasteur (CIBU), j INSERM U1002 and k Centre d’Infectiologie Necker-Pasteur, Paris , France

0.0004). The median duration of treatment to obtain com-plete remission was 2.4 (range 0.9–6.5) and 3.8 months (range 1.6–7.4) in stage 1 and 2 patients, respectively, and 6.2 and 12 months in the 2 stage 3 patients. Main adverse events of the treatments were gastrointestinal disorders (64% of patients) and vaginal candidiasis (35% of females). Reversible tendi-nopathy and hepatitis occurred in 4 and 1 patient, respec-tively. Conclusions: Complete remission of refractory HS can be obtained using broad-spectrum antibiotics and Hurley staging is a prognostic factor of response to the treatment.

Copyright © 2010 S. Karger AG, Basel

Introduction

Hidradenitis suppurativa (HS) is an orphan follicular inflammatory disease of the apocrine-gland-bearing ar-eas of the skin with an estimated prevalence of 0.2–1% [1] .

Key Words

Hidradenitis suppurativa � Antibiotherapy � Rifampin � Moxifloxacin � Metronidazole

Abstract

Background: Antibiotics have been shown to improve hi-dradenitis suppurativa (HS) patients but complete remission is rare using these treatments. Objective: To assess the effi-cacy and safety of a combination of oral rifampin, moxifloxa-cin and metronidazole in long-lasting refractory HS. Meth-

ods: We retrospectively studied 28 consecutive HS patients including 6, 10 and 12 Hurley stage 1, 2 and 3 patients, respec-tively. Complete remission, defined as a clearance of all in-flammatory lesions including hypertrophic scars, was the main outcome criterion of the study. Results: Complete re-mission was obtained in 16 patients, including 6/6, 8/10 and 2/12 patients with Hurley stage 1, 2 and 3, respectively (p =

Received: June 25, 2010 Accepted after revision: September 27, 2010 Published online: November 25, 2010

Dr. Olivier Join-Lambert Laboratoire de Microbiologie, Hôpital Necker-Enfants maladesAssistance publique – Hôpitaux de Paris 161, rue de Sèvres, FR–75743 Paris Cedex 15 (France) Tel. +33 144 494 961, Fax +33 144 494 960, E-Mail olivier.join-lambert @ inserm.fr

© 2010 S. Karger AG, Basel1018–8665/10/0000–0000$26.00/0

Accessible online at:www.karger.com/drm

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Join-Lambert et al. Dermatology 2

The disease is characterized by recurrent abscesses lead-ing to large chronic suppurating lesions in severer cases [1] . The disease usually begins after puberty, and a famil-ial history is present in 30–40% of the patients [2] .

The pathophysiology of HS is unclear and there is no satisfactory medical treatment. Wide surgical resection of lesions remains the cornerstone treatment [3, 4] , but it does not prevent relapses of the disease in other anatom-ical sites. Short courses of antibiotics or a low-dose regi-men of rifampin and clindamycin for 10 weeks are used as supportive care but are usually unable to completely heal HS lesions [5–7] .

In the absence of any validated therapies, we treated long-lasting HS patients with more intensive compas-sionate antimicrobial treatments at the Centre d’Infec-tiologie Necker-Pasteur based on the microbiology of HS lesions [8–13] . The aim of this study was to assess the ef-ficacy and safety of a therapeutic strategy based on an oral antimicrobial combination that included rifampin, moxifloxacin and metronidazole in 28 consecutive HS patients.

Methods

Patients We reviewed the medical records of all adult patients with a

diagnosis of HS at the Centre d’Infectiologie Necker-Pasteur ac-cording to the criteria of von der Werth et al. [14] , who received an antimicrobial treatment based on the combination of ri-fampin (10 mg/kg once daily), moxifloxacin (400 mg daily) and metronidazole (500 mg t.i.d.) from September 2008 to October 2009.

Twenty-eight consecutive patients were eligible, including 6 Hurley stage 1, 10 Hurley stage 2 and 12 Hurley stage 3 patients ( table 1 ). All patients had long-lasting refractory disease and gave their informed consent to receive this antimicrobial regimen. Most patients had been previously treated unsuccessfully with short courses of antimicrobials and/or surgical drainage and 35% had previously undergone wide surgical excision of lesions. Topi-cal and systemic corticosteroids as well as nonsteroidal anti-in-flammatory drugs and topical antibiotics were always stopped be-fore starting the treatment.

Altogether, the total number of HS-affected areas among the 28 patients was 106, including 36 Hurley stage 1, 47 Hurley stage 2 and 23 Hurley stage 3 lesional areas.

Treatments The rifampin-moxifloxacin-metronidazole combination was

given for 6 weeks and metronidazole was stopped thereafter to avoid neurological complications ( fig. 1 ). Clinical evaluation of the rifampin-moxifloxacin combination was then assessed every 6 weeks, and the treatment was continued as long as the patient’s clinical status continued to improve without serious side effects.

When a complete remission was obtained, the rifampin-mox-ifloxacin combination was continued for at least 6 weeks as a con-solidation treatment. At the end of this consolidation treatment, secondary prophylaxis consisting in trimethoprim-sulfamethox-azole (400 mg/80 mg daily) or doxycycline (100 mg/day) was em-pirically prescribed.

Among the 28 patients included in this study, 14 received a 2-week induction therapy consisting in intravenous ceftriaxone (1 g daily) and oral metronidazole (500 mg t.i.d.; table 2 ). This in-duction therapy was predominantly given to patients with the se-vere form of the disease (1/6 Hurley stage 1 patient, 6/10 Hurley stage 2 patients and 7/12 Hurley stage 3 patients).

Efficacy and Duration of Treatments The initial severity of the disease was assessed using Hurley’s

clinical severity staging [15] : stage 1 = abscess formation, single or multiple without sinus tracts or hypertrophic scars; stage 2 = re-current abscesses with sinus tract and scarring formation, single or multiple widely separated lesions; stage 3 = diffuse or near-ly diffuse involvement or multiple interconnected tracts or ab-scesses across the entire area. The patient’s global Hurley staging corresponds to the severest HS-affected area.

Since there is no validated retrospective HS score, we used the Hurley clinical severity staging to assess the evolution of HS le-sions under treatment at each follow-up visit. Although this sever-ity score was not intended to be used as such, the Hurley staging was in good agreement with the clinical evolution of the lesions under treatment. When a favorable outcome was obtained, pain disappeared first and suppurative lesions stopped oozing. Then

Table 1. HS patients’ characteristics

Number of patients 28Sex ratio (males/females) 0.4 (8/20)Age1, years 30 (20–53)Age at onset of the disease1, years 18 (8–46)Duration of HS1, years 13.5 (1–28)Familial history of HS2 8 (29)History of acne2 17 (60)Previous treatments2

Antibiotics 27 (93)Surgical drainage 25 (86)Wide surgical excisions 10 (35)

Patient’s Hurley severity staging, number of patientsHurley stage 1 6Hurley stage 2 10Hurley stage 3 12

Number of HS-affected areas1 4 (1–7)Years of evolution of HS-affected areas (n = 106)1

Hurley stage 1 areas (n = 36) 3.0 (0.5–7)Hurley stage 2 areas (n = 47) 3.0 (0.5–18)Hurley stage 3 areas (n = 23) 5.0 (0.5–18)

HS areas’ localization, % of all areasGroin 41Axillae 27Perianal area 14Buttocks 9Other areas of the skin 9

1 Median with range in parentheses.2 Number with percentage in parentheses.

Antimicrobial Treatment of Hidradenitis Suppurativa

Dermatology 3

the size of indurated lesions (hypertrophic scars and nodules) progressively decreased as they melted and became soft. A closing of subcutaneous fistulas could be observed and the color of the surrounding skin returned to normal. A complete remission of lesions was defined as the absence of any persisting active clinical lesions including hypertrophic and/or oozing plaques at 2 con-secutive follow-up visits. Indolent epidermal cysts, single- or dou-ble-end comedos as well as soft nonoozing flesh-colored skin folds were considered as sequelae that did not require continua-tion of the antimicrobial treatment.

A partial response was defined as (i) either a decrease in the patient’s Hurley staging or (ii) a decrease in the number of HS-affected sites observed at 2 consecutive follow-up visits. Combi-nation therapy was stopped either because of side effects or when no further clinical improvement was observed at a 6-week inter-val.

Adverse Events The tolerance and safety of the treatment were assessed clini-

cally at each follow-up visit. Pretherapeutic investigations includ-ed an electrocardiogram, and monitoring of leukocytes, platelets and liver enzymes was performed during treatment.

Statistical Analysis The main outcome endpoint of our study was the achievement

of a complete remission in patients. However, since the patient’s Hurley staging does not take into account an eventual heterogene-ity of response of each HS-affected area, the efficacy of the treat-ment was also assessed for each individual lesional site. Prognos-

tic factors of complete remission were assessed either by a Fisher exact test or a Wilcoxon rank test according to the qualitative or quantitative variable type. Statistical significances of factors as-sociated with complete remission at the individual lesional site were also tested by a logistic regression using the generalized es-timating equation approach [16] to take into account the depen-dence of observations pertaining to the same subject. Multivari-ate analyses were also performed by logistic regression for either independent or clustered data. The probabilities of complete re-mission of patients or lesional sites according to time of treatment were estimated by the Kaplan-Meier method and the curves com-pared respectively by a log-rank test and a Cox-Wei hazard regres-sion for clustered data [17] . A p value ! 0.05 was considered statis-tically significant. Computations were performed with SAS 9.2 (SAS Institute Inc., Cary, N.C., USA) and R 2.10.1 (http://www.r-project.org).

Results

Efficacy of the Treatments A complete remission was obtained in 16 patients

(57%), including 6/6, 8/10 and 2/12 Hurley stage 1, 2 and 3 patients, respectively ( tables 2 and 3 ). The median dura-tion of treatment to obtain complete remission was short-er in mild forms of the disease: 2.4 (range 0.9–6.5) months

2007–2009: 28 consecutive refractory HS patients(Hurley stage 1: n = 6, Hurley stage 2: n = 10, Hurley stage 3: n = 12)

Oral rifampin+ moxifloxacin

+ metronidazole(6 weeks)

n = 14

Relapse orlocalized resistance

(n = 4)

Ceftriaxone (i.v.) + oral metronidazole(2 weeks) n = 14

Oral rifampin + moxifloxacin + metronidazole(4 weeks) n = 14

Rifampin + moxifloxacin (n = 28)

Follow-up/6 weeks:

Improvement of lesions

Rifampin + moxifloxacin (6 weeks)

Complete remission (n = 16) Partial response (n = 12)

Consolidation treatment:Rifampin + moxifloxacin (6 weeks)

Persisting complete remission (n = 16)

Secondary prophylaxis

Fig. 1. Flowchart of patients and treat-ments used in this study. Intravenous cef-triaxone: 1 g/day; oral metronidazole:500 mg t.i.d.; oral rifampin: 10 mg/kg/day; oral moxifloxacin: 400 mg/day; oral tri-methoprim-sulfamethoxazole: 400 mg/80 mg/day; oral doxycycline: 100 mg/day. Metronidazole was not prescribed for more than 6 weeks to prevent neurological side effects.


Table 2. Analysis of treatments

Pa-tientNo.

B aseline evaluation

Description of treatments Efficacy of treatments

Follow-up after complete remission

HS max.duration 1(years)

N° of HSareas

lines of treatment duration2 (months)

finalHurleystaging

final HSareas

dura-tion (months)

prophy-laxis

relapses3 Hurley staging at the end of follow-up

Hurley stage 1 patients (n = 6)1 0.5 1 RMoM, RMo 1.7 0 0 (0) 8 SXT M2 (st. 1), 2 months 02 0.5 1 RMoM, RMo 0.9 0 0 (0) 7 SXT none 03 0.8 3 CM, RMoM 1.5 0 0 (0) 4 SXT none 04 4 3 RMoM, RMo 1.2 0 0 (0) 12 DOX M5 (st. 1), 3 months 05 3 5 RMoM, RMo 2.1 0 0 (0) 2 SXT none 06 8 5 RMoM, RMo4, RMoM 6.5 0 0 (0) 6 SXT none 0

Hurley stage 2 patients (n = 10)7 7 1 CM, RMoM, RMo 2.8 0 0 (0) 11 SXT M8 (st. 1), 1 month 08 8 2 CM, RMoM, RMo 4.4 0 0 (0) 6 SXT M2 (st. 1), 4 months 05, 6

9 2 2 RMo7, RMoM, RMo 6.5 0 0 (0) 9 SXT M2 (st. 1), 1.5 months 010 4 2 CM, RMoM 3.3 08 0 (0) 3 SXT M2 (st. 1), 0.5 months 011 5 4 RMoM, RMo 2.5 0 0 (0) 6 SXT none 012 3 5 CM, RMoM, RMo 2.6 0 0 (0) 0 n.a. n.a. 013 6 5 CM, RMoM, RMo 1.6 0 0 (0) 0 n.a. n.a. 014 4 6 RMo7, RMoM, RMo 5.6 0 0 (0) 5 none M5 (st. 2), none 215 2 3 CM, RMoM, RMo 2.3 18 2 (66) n.a.16 3 3 RMoM, RMo 1.0 29 2 (66) n.a.

Hurley stage 3 patients (n =12)17 10 3 RMoM, RMo4, RMoM, RMo 11.9 0 0 (0) 4 SXT none 018 0.9 7 CM, RMoM, RMo 6.1 0 0 (0) 2 SXT none 019 8 6 CM, RMoM, RMo 4.0 18 1 (17) n.a.20 7 3 CM, RMoM, RMo 2.6 1 2 (66) n.a.21 3 4 CM, RMoM, RMo4, RMoM 4.9 2 4 (100) n.a.22 3 4 RMoM 1.0 210 4 (100) n.a.23 13 4 RMoM, RMo 4.6 2 3 (75) n.a.24 18 4 CM, RMoM 3.0 28 4 (100) n.a.25 7 5 CM, RMoM, RMo 2.5 2 2 (40) n.a.26 0.5 5 RMoM, RMo4, RMoM, RMo 5.8 25 1 (20) n.a.27 3 5 RMo7, RMoM, RMo 6.1 3 3 (60) n.a.28 5 5 CM, RMoM, RMo4 5.7 3 3 (60) n.a.

CM = Intravenous ceftriaxone and oral metronidazole for2 weeks; RMoM = oral rifampin-moxifloxacin-metronidazole for a maximum duration of 6 weeks; RMo = oral rifampin-mox-ifloxacin for 6 weeks or more; SXT = oral trimethoprim-sulfa-methoxazole; DOX = oral doxycycline; st. = stage; n.a. = not ap-plicable. Final HS areas given as numbers with percentage of ini-tial number in parentheses.

1 Duration of continuous active lesions (and not of the disease) at the onset of treatment.

2 In case of complete remission, the duration of the treatment does not include the duration of the consolidation treatment that was given after complete remission.

3 Months after the end of the consolidation treatment (Hurley staging of the relapse), duration of the treatment of the relapse in order to obtain a new complete remission.

4 Relapse after discontinuation of metronidazole.5 Persisting active fistula.6 Surgical treatment.7 A partial remission was obtained with the rifampin-moxi-

floxacin combination.8 Treatment stopped for tendinitis.9 Treatment stopped for gastrointestinal intolerance.10 Treatment stopped for interactions with concomitant non-

anti-infectious treatments.


Dermatology 5

for stage 1 patients, 3.8 (1.6–7.4) months for stage 2 pa-tients, 6.2 and 12 months for the 2 Hurley stage 3 patients whose lesions healed completely ( fig. 2 a). Among all pa-rameters that were tested by univariate analysis ( table 4 ), only the patient’s Hurley staging and the inguinofemoral localization of the disease were poor prognostic factors of complete remission. However, only the patient’s Hurley staging remained significant when these 2 factors were tested simultaneously (p = 0.01).

A partial response was observed in all other patients including 2/8 Hurley stage 2 patients and 10/12 Hurley stage 3 patients ( tables 2 and 3 ). The 2 Hurley stage 2 pa-tients early stopped the treatment due to adverse events (tendinitis and gastrointestinal intolerance) after 2.3 months and 1 month of treatment, respectively. The clin-ical status of the 10 Hurley stage 3 patients who did not obtain complete remission was also significantly im-proved with a final Hurley staging of 1 for 2 patients and of 2 for 7 patients. The Hurley staging was unchanged for 2 Hurley stage 3 patients at the end of the treatment, but a complete remission of 2/5 affected areas was obtained in both patients.

Analysis of the efficacy of the treatments on the 106 HS-affected areas of the 28 patients showed that a com-plete remission was obtained in 92, 64 and 48% of Hur-ley stage 1, 2 and 3 HS-affected areas ( table 3 ). The me-dian duration of treatments to obtain complete remis-sion for an individual HS area was 1.9 (range 0.9–6.5) months, 2.6 (1.1–6.5) and 4 (2.6–11.9) months for Hurley stage 1, 2 and 3 HS areas, respectively. Among all pa-rameters that were tested by univariate analysis ( table 4 ), only the Hurley staging of HS areas (p = 0.013) and the

Hurley staging of patients (p = 0.005) were prognostic factors for complete remission. However, only the pa-tient’s Hurley staging remained significant when these 2 factors were tested simultaneously (p = 0.01). Indeed, although the complete remission rate of Hurley stage 1 areas was not significantly affected by the Hurley stag-ing of patients ( fig. 2 b), the remission rate of Hurley stage 2 areas was higher in Hurley stage 2 patients than in Hurley stage 3 patients (85 vs. 48%, respectively) dem-onstrating a heterogeneity of responses among Hurley stage 2 areas depending on the global patient’s Hurley staging ( fig. 2 c).

Follow-Up after Complete Remission Among the 16 patients who achieved complete remis-

sion, no follow-up was available for 2 patients who start-ed their secondary prophylaxis at the time of analysis of medical records ( table 2 ). The follow-up period of the 14 other patients varied from 2 to 12 months ( table 2 ). Thir-teen of them were given secondary prophylaxis consist-ing either in trimethoprim-sulfamethoxazole (12 pa-tients) or doxycycline (1 patient). A relapse of the disease occurred in 7/14 patients ( table 2 ), including 6 patients under secondary prophylaxis. Lesions always relapsed in a previously affected area. These lesions were fewer in number (usually only 1 area was affected) and respond-ed rapidly to a new treatment, resulting in complete re-mission in 5/7 patients in 1.5–3 months. One patient (No. 8) required surgery for a 4-cm-long closed perianal fistula that did not respond to the treatment, and the last one (No. 14) was lost to follow-up after initiation of a new treatment. The duration of follow-up of the 7 pa-tients who did not relapse varied from 2 to 6 months ( table 2 ), demonstrating that a prolonged complete re-mission can be obtained in HS patients using this treat-ment strategy.

Adverse Events The most common adverse events of the treatments

were gastrointestinal disorders (64% of patients), pre-dominantly including nausea and mild diarrhea. Two pa-tients reported mild dizziness under metronidazole treat-ment. Vaginal candidiasis occurred in 7 patients (35% of females). Moxifloxacin-associated tendinitis was report-ed in 4 patients (14%) and resulted in early treatment in-terruption. Rifampin was stopped in 2 patients, 1 due to hepatitis and 1 for an interaction with an anti-antiepilep-tic treatment.

Table 3. Global efficacy of rifampin-moxifloxacin-metronidazole combination treatments in HS

Baselineevaluation

E fficacy of the treatment

Hurley staging

n completer emissions

partial responses (final Hurley stage)

1 2 3

PatientsStage 1 6 6 (100%) 0 0 0Stage 2 10 8 (80%) 1 (10%) 1 (10%) 0Stage 3 12 2 (17%) 2 (17%) 6 (50%) 2 (17%)

HS-affected areasStage 1 36 33 (92%) 3 (8%) 0 0Stage 2 47 30 (64%) 12 (26%) 5 (10%) 0Stage 3 23 11 (47%) 5 (22%) 5 (22%) 2 (9%)


0a

0.2

0.4

0.6

0.8

1.0

Hurley stage 1 patients (n = 6)

Prob

abili

ty o

f com

plet

e re

mis

sion

Hurley stage 2 patients (n = 10)Hurley stage 3 patients (n = 12)

0b

0.2

0.4

0.6

0.8

1.0

Hurley stage 1 patients (n = 18)Hurley stage 1 areas in

Prob

abili

ty o

f com

plet

e re

mis

sion

Hurley stage 2 patients (n = 13)Hurley stage 3 patients (n = 5)

0

0c

2 4 6Months after initiation of treatments

8 10 12

0.2

0.4

0.6

0.8

1.0 Hurley stage 2 areas inHurley stage 2 patients(n = 20)

Prob

abili

ty o

f com

plet

e re

mis

sion

Hurley stage 2 areas inHurley stage 3 patients(n = 27)

Hurley stage 3 areas(n = 23)

d

Fig. 2. Kinetics of complete remission. a Probability of complete remission of patients according to Hurley staging (log rank test,p = 0.01). b Probability of complete remission of Hurley stage 1 areas in Hurley stage 1, 2 and 3 patients (Cox-Wei hazard regres-sion, p = NS). c Probability of complete remission of Hurley stage 2 and 3 areas in Hurley stage 2 and 3 patients (Cox-Wei hazard regression, p = 0.01). d Clinical efficacy of the rifampin-moxiflox-acin-metronidazole combination therapy in a Hurley stage 3 pa-

tient (No. 18 in table 2). Bilateral axillary Hurley stage 3 lesions and 1 inguinal stage 2 lesional area are shown before treatment (photographs 1–3) and at the time of complete remission (photo-graphs 4–6). Before treatment, the patient demonstrated a limited ability to move the arms because of painful and indurated sup-purating lesions. At the end of the treatment, only soft nonoozing painless skin folds without any persisting induration of the skin were present.


Dermatology 7

Discussion

Since the first description of HS by Verneuil [18] in the late 19th century, the etiology of this syndrome remains enigmatic and HS is considered an inflammatory follicu-

lar disease with frequent superinfections [1] . Various nonexclusive pathophysiological hypotheses have been proposed for HS, including genetic, microbial, hormonal and immunological factors [19] , and the different medi-cal therapeutic options that have been used to treat pa-

Table 4. Prognostic factors associated with complete remissiona Complete remission of patients

Patient outcome p value1 p value2

complete remission(n = 16)

partial response(n = 12)

Age of patients, years 32.5 (20–53) 28.0 (20–49) 0.40Age of onset of the disease, years 17.5 (8–46) 19.0 (8–35) 0.98Years of evolution of HS 14.0 (1–26) 10.5 (3–24) 0.44Sex ratio, M/F 0.6 0.2 0.40Familial history of HS 5 (31) 3 (25) 1.00History of acne 10 (63) 7 (58) 1.00Number of HS-affected areas 3.0 (1–7) 4.0 (3–6) 0.22Patient’s Hurley staging (stage 1/2/3) 6/8/2 0/2/10 0.0004 0.01Localization of HS areas

Inguinofemoral area 10 (63) 12 (100) 0.0024 0.97Axillae 8 (50) 9 (75) 0.25Perianal area 8 (50) 7 (58) 0.72Buttocks 4 (25) 2 (17) 0.67

b Complete remission of HS-affected areas

HS area outcome p value3 p value3

complete remission(n = 74)

partial response(n = 32)

Patient characteristicsPatient’s age, years 28 (20–53) 28 (20–49) 0.35Age of onset of the disease, years 17 (8–46) 19 (8–35) 0.45Years of evolution of HS 12 (1–28) 10.5 (3–24) 0.75Sex ratio, M/F 0.64 0.28 0.44Familial history of HS 26 (35) 8 (25) 0.47History of acne 42 (57) 21 (65) 0.94Number of HS-affected areas 5 (1–7) 4 (3–6) 0.81Patient’s Hurley staging 0.005 0.01

HS-affected areas characteristicsYears of evolution of HS areas, years 3 (0.5–13) 3 (0.5–18) 0.28HS areas Hurley staging 0.013 0.90

Localization of HS areasInguinofemoral area 25 (34) 16 (50) 0.44Axillae 20 (27) 8 (25) 0.82Perianal area 10 (14) 5 (16) 0.89Buttocks 6 (8) 3 (9) 0.57

Da ta are given as numbers with percentages in parentheses or as medians with ranges in parentheses.1 Fisher exact test (qualitative variables) or Wilcoxon rank test (quantitative variables).2 Logistic regression.3 Generalized estimating equation logistic regression.


tients, including retinoids, antibiotics, antiandrogens, high-dose zinc salts and recently anti-tumor-necrosis-factor- � treatments, are not satisfactory [20] . In this study, we demonstrate that complete healing of long-last-ing HS lesions can be achieved using an empirical, broad-spectrum antimicrobial treatment strategy based on the combination of rifampin, moxifloxacin and metronida-zole. This clinical observation is consistent with the mi-crobial pathophysiological hypothesis of HS, where le-sions could result from an abnormal relationship between the host and its own skin microflora [19] . The association of HS and Crohn disease has recently raised the issue that HS may also be a ‘barrier disease’ [21] , and the low patho-genicity of bacteria associated with HS lesions is consis-tent with this hypothesis [8] .

Our approach was based on the hypothesis that the ineffectiveness of the usual antimicrobial treatments in HS may be due to an inadequate antimicrobial spectrum or to the poor diffusion of antibiotics into infected sites. After the preliminary report of Mendonca and Griffiths [7] , who suggested that a low dosing regimen of rifampin (300 mg b.i.d.) and clindamycin (300 mg b.i.d.) could be useful in HS, we used this strategy to treat patients. Un-fortunately, this combined treatment only transitorily

improved severe HS cases, a finding that was confirmed recently in two retrospective studies [5, 6] . Since various bacteria of the skin flora such as Propionibacterium acnes and coagulase-negative staphylococci [8] , but also strep-tococci of the Streptococcus milleri group and miscella-neous anaerobes have been cultured from chronic HSlesions [8–12] , we moved to a combination of rifampin(10 mg/kg daily) and moxifloxacin (400 mg daily). In-deed, both antibiotics are bactericidal, have a wide anti-microbial spectrum that includes anaerobes and have good diffusion properties [22] . Nevertheless, only few pa-tients reached complete remission with this treatment. It has been reported that some Gram-negative anaerobic species are naturally resistant or have intermediate sus-ceptibility to moxifloxacin, and that an alteration of the pharmacokinetics of moxifloxacin is observed in asso-ciation with rifampin [23, 24] . Therefore, and taking into account the fact that the addition of metronidazole (a po-tent antianaerobic drug [25] ) allowed to obtain complete remissions in some patients, the triple combination of ri-fampin, moxifloxacin and metronidazole was used there-after to optimize the treatment. The duration of the treat-ment was adapted to the clinical response of each patient since, in our experience, a relapse of the disease was ob-

Hurley stage 1patients

Rifampin + moxifloxacinuntil complete remission or relapse

Ceftriaxone (i.v.) + metronidazole3 weeks

Rifampin + moxifloxacin + metronidazole

Relapse or partial response

Intensification treatment

Complete remission

Consolidation treatment:Rifampin + moxifloxacin

(6–12 weeks)

Persisting complete remission:Consider secondary prophylaxis(trimethoprim-sulfamethoxazole

or doxycycline)

One persisting HS area:Consider surgery



3 weeks 6 weeks

or

6 weeks

Fig. 3. Current antimicrobial treatment strategy of HS used at the Centre d’Infec-tiologie Necker-Pasteur, Paris, France. Hurley stage 3 patients are significantly improved using this treatment strategybut complete remission is seldom achieved in all HS-affected sites despite prolonged treatments.


Dermatology 9

served in all patients who stopped their antimicrobial treatment before complete remission. In 4 patients in-cluded in this study ( table 2 ), a relapse was observed after discontinuation of metronidazole and the reintroduction of metronidazole resulted in complete remission in 2 of these patients. These findings suggest that a prolonged and optimized antimicrobial treatment including anaer-obic bacteria is mandatory to treat HS lesions [10] .

We found that the patient’s Hurley severity staging was the only prognostic factor of response to the treat-ment and that the duration of treatments to obtain com-plete remission tended to be longer for severer cases. The scarring process that is associated with chronic HS le-sions, including fibrosis and formation of epithelialized sinus tracts or epidermal cysts, probably limits the diffu-sion of antibiotics to the infected site and accounts for the low response rate of Hurley stage 3 patients. Besides, we observed that relapses always occurred in previously af-fected sites in 50% of patients with complete remission, but the same treatment allowed to obtain complete remis-sion again. These data suggest that relapses could result either from persisting ‘dormant’ bacteria and/or from a new colonization of HS scars after discontinuation of the treatment.

Our study has limitations. First, the retrospective and monocentric design of this report may introduce bias. However, we included all consecutive patients who re-ceived the rifampin-moxifloxacin-metronidazole combi-nation over a short period of time, and in the absence of demonstrated activity of antibiotics in HS, only treated patients with long-lasting lesions (median duration of HS: 13.5 years, median duration of lesions: 3 years) who were refractory to previous medical treatments. In addi-tion, the simultaneous remission of all lesions in patients with severe long-lasting HS is highly unlikely to occur spontaneously in a short period of time. Finally, although no definite conclusions should be drawn from this short series of patients, the benefit of this treatment strategy was maintained for months after discontinuation of the treatment in patients with complete remission since re-lapses that occurred in 50% of patients were less severe and responded again to new antimicrobial treatments.

The clinical observation that HS can respond to anti-microbial treatments opens an avenue for future research whose primary aims should be to reduce the duration of the treatments and to prevent relapses or recurrences of the disease. Future studies should focus on the precise microbiology of HS both at baseline and in case of clini-cal resistance, and try other treatment strategies to re-duce the duration of treatments and to improve the re-

sponse rate of severe HS cases. In an attempt to reach these goals, the treatment strategy currently used to treat Hurley stage 2 and stage 3 patients at the Centre d’Infec-tiologie Necker-Pasteur systematically includes an intra-venous induction treatment consisting in ceftriaxone and oral metronidazole for 3–4 weeks ( fig. 3 ). In case of re-lapse of the disease after discontinuation of metronida-zole, an intensification treatment is given to patients, consisting either in a reintroduction of metronidazole in association with rifampin and moxifloxacin, or in a new induction treatment using intravenous broad-spectrum betalactams. Surgery is systematically discussed for pa-tients who do not respond to the intensification treat-ment.

To conclude, this study demonstrates that complete re-mission of severe HS can be achieved using broad-spec-trum antimicrobial treatment and that the benefit of these treatments can be prolonged thereafter. Prospective studies are required to confirm these data, and to deter-mine the optimal strategy to prevent relapses of the dis-ease.

Acknowledgements

The authors would like to thank Prof. Eric Pamer for kindly reviewing the manuscript and the French Association of HS Pa-tients (Association Française pour la Recherche sur l’Hidrosadé-nite suppurée) for their constant support.

Disclosure Statement

None of the authors has any financial conflict of interest.

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Efficacy of Rifampin-Moxifloxacin-Metronidazole Combination Therapy in Hidradenitis Suppurativa

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