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. 2018 Aug 23;2018(8):CD012118. doi: 10.1002/14651858.CD012118.pub2

5. Paradoxical reactions in Buruli ulcer: description of studies and main results.

Regimen Study Design Comparisons Surgery N Sex
(M:F) 		Age Lesion types Incidence of PR Onset time of PR Our observation
RFP and SM Sarfo 2010 POS 1 group: RFP + SM for 8 weeks (8RS) When indicated
(post‐Rx)		 160 66:94 Median 12 years
(1 to 75)		 Ulcer: 86 (54%)
Nodule: 36 (22%)
Plaque: 14 (9%)
Oedema: 24 (15%)		 3/159 (1.9%)a At weeks 4, 6, 12 Approximately 1 in 20 participants treated with 8RS developed PR. 2 cases occurred during Rx and 1 case occurred post‐Rx.
RFP and SM
or
RFP and SM
plus
RFP and CAM		 Barogui 2016 POS 1 group:

  1. RFP + SM for 8 weeks (n = 166)

  2. RFP + SM for 4 weeks followed by RFP + CAM for 4 weeks (n = 75)

 When indicated 241 88:153 Mean (SD) 16(13) years Ulcer: 108 (45%)
Nodule: 32 (13%)
Plaque: 56 (23%)
Oedema: 11 (5%)
Mixed: 34 (14%)		 52/241 (22%)b Between week 8 and 12 Approximately 1 in 5 participants treated with Rx developed PR between week 8 and 12.
RFP and SM
plus
RFP and CAM		 Phillips 2014a POS 1 group: RFP + SM for 2 weeks (2RS) followed by RFP + CAM for 6 weeks (6RC) When indicated 43 18:25 Median 14 years
(5 to 70)		 Ulcer: 20 (47%)
Nodules: 14 (32%)
Plaque: 9 (21%)		 4/41 (9.3%)c Median 12 weeks (range, 4 to 32 weeks) Approximately 1 in 10 participants treated with 2RS + 6RC developed PR at median 12 weeks after start of treatment.
Combination of RFP, CIPRO, CAM, ETB, AMK, MOX O'Brien 2012 POS 8 groups: Weeks of

  1. RFP + CIPRO (n = 55)

  2. RFP + CAM (n = 21)

  3. RFP + CAM + ETB (n = 5)

  4. CIPRO + CAM (n = 4)

  5. RFP + MOX (n = 2)

  6. CAM + ETB (n = 1)

  7. RFP + ETB + AMK (n = 1)

  8. CAM (n = 1)

 All 90 NR NR NR 8/90 (8.9%)d Median 48 days (range, 14 to 85 days) Approximately 1 in 10 participants treated with different regimens of Rx developed PR at median 8 weeks after start of treatment.
Combination of RFP, CAM, ETB, AMK, MOX O'Brien 2013b POS 1 group: received Rx When indicated 156 86:70 < 15 years: 13 (8%);
15 to 60 years: 62 (40%);
> 60 years: 81 (52%)		 Ulcer: 137 (87.8%)
Nodules: 10 (6.4%)
Oedema: 9 (5.8%)		 32/156 (21%)e Median 39 days (IQR 20 to 73 days) Approximately 1 in 5 participants treated with different regimens of Rx developed PR at 5.6 weeks after start of treatment.
RFP and either CIPRO, CAM, or MOX Friedman 2016 POS 3 groups: Weeks of

  1. RFP + CIPRO (n = 80)

  2. RFP + CAM (n = 50)

  3. RFP + MOX (n = 2)

 Limited surgical debridement when indicated 132 75:57 Median 49 years (1 to 95) Ulcer: 110 (83.3%)
Nodule: 9 (6.8%)
Oedema: 10 (7.6%)
Plaque: 3(2.3%)		 34/132 (26%)d Median 48 days (IQR 29 to 69 days) Approximately 1 in 4 participants treated with different regimens of Rx developed PR at median 8 weeks after start of treatment.

aOne death.
 b37/166 (22%) received RFP + CIPRO; 15/75 (20%) received RFP + CAM.
 c2 participants lost to follow‐up.
 dResults not available for each individual regimen.
 ePredictors of paradoxical reactions (multivariable analysis): age ≥ 60 years (risk ratio (RR) 2.84, 95% confidence interval (CI) 1.12 to 7.17; P = 0.03), oedematous lesion (RR 3.44, 95% CI 1.11 to 10.70; P = 0.03), use of amikacin in the initial Rx regimen (RR 6.33, 95% CI 2.09 to 19.18; P < 0.01).

Abbreviations: AMK, amikacin; CAM, clarithromycin; CIPRO, ciprofloxacin; ETB, ethambutol; IQR, interquartile range; Lab, laboratory confirmation; MOX, moxifloxacin; NR, not reported; POS, prospective observational study; PR, paradoxical reactions; RCT, randomized controlled trial; RFP, rifampicin; Rx, treatment; SD, standard deviation; SM, streptomycin.