Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections

BMC Infectious Diseases

Eugene Athan³  Richard Rahdon²  Andrew Hughes³  Peter Callan²  Anthony McDonald²  Aaron Walton³  N Deborah Friedman³  Mike Robson¹  Daniel P O’Brien⁴ 

[1] Department of Pathology, Pathcare, Geelong, Australia;Department of Plastic Surgery, Barwon Health, Geelong, Australia;Department of Infectious Diseases, Barwon Health, Geelong, Australia;Manson Unit, Médecins Sans Frontières, London, United Kingdom

关键词: Treatment;    Diagnosis;    Clinical;    Incidence;    Predictors;    Antibiotics;    Paradoxical reactions;    Mycobacterium ulcerans;   

Others  :  1145844
DOI  :  10.1186/1471-2334-13-416

 received in 2013-05-21, accepted in 2013-08-27,  发布年份 2013

【 摘 要 】

Background

Paradoxical reactions from antibiotic treatment of Mycobacterium ulcerans have recently been recognized. Data is lacking regarding their incidence, clinical and diagnostic features, treatment, outcomes and risk factors in an Australian population.

Methods

Data was collected prospectively on all confirmed cases of M. ulcerans infection managed at Barwon Health Services, Australia, from 1/1/1998-31/12/2011. Paradoxical reactions were defined on clinical and histological criteria and cases were determined by retrospectively reviewing the clinical history and histology of excised lesions. A Poisson regression model was used to examine associations with paradoxical reactions.

Results

Thirty-two of 156 (21%) patients developed paradoxical reactions a median 39 days (IQR 20-73 days) from antibiotic initiation. Forty-two paradoxical episodes occurred with 26 (81%) patients experiencing one and 6 (19%) multiple episodes. Thirty-two (76%) episodes occurred during antibiotic treatment and 10 (24%) episodes occurred a median 37 days after antibiotic treatment. The reaction site involved the original lesion (wound) in 23 (55%), was separate to but within 3 cm of the original lesion (local) in 11 (26%) and was more than 3 cm from the original lesion (distant) in 8 (19%) episodes. Mycobacterial cultures were negative in 33/33 (100%) paradoxical episodes. Post-February 2009 treatment involved more cases with no antibiotic modifications (12/15 compared with 11/27, OR 5.82, 95% CI 1.12-34.07, p = 0.02) and no further surgery (9/15 compared with 2/27, OR 18.75, 95% CI 2.62-172.73, p < 0.001). Six severe cases received prednisone with marked clinical improvement. On multivariable analysis, age ≥ 60 years (RR 2.84, 95% CI 1.12-7.17, p = 0.03), an oedematous lesion (RR 3.44, 95% CI 1.11-10.70, p=0.03) and use of amikacin in the initial antibiotic regimen (RR 6.33, 95% CI 2.09-19.18, p < 0.01) were associated with an increased incidence of paradoxical reactions.

Conclusions

Paradoxical reactions occur frequently during or after antibiotic treatment of M. ulcerans infections in an Australian population and may be increased in older adults, oedematous disease forms, and in those treated with amikacin. Recognition of paradoxical reactions led to changes in management with less surgery, fewer antibiotic modifications and use of prednisolone for severe reactions.

【 授权许可】

   
2013 O’Brien et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Boyd SC, Athan E, Friedman ND, Hughes A, Walton A, Callan P, McDonald A, O'Brien DP: Epidemiology, clinical features and diagnosis of mycobacterium ulcerans in an Australian population. The Medical journal of Australia 2012, 196(5):341-344.
• [2]Guarner J, Bartlett J, Whitney EA, Raghunathan PL, Stienstra Y, Asamoa K, Etuaful S, Klutse E, Quarshie E, van der Werf TS, et al.: Histopathologic features of mycobacterium ulcerans infection. Emerging infectious diseases 2003, 9(6):651-656.
• [3]Coutanceau E, Decalf J, Martino A, Babon A, Winter N, Cole ST, Albert ML, Demangel C: Selective suppression of dendritic cell functions by mycobacterium ulcerans toxin mycolactone. The Journal of experimental medicine 2007, 204(6):1395-1403.
• [4]World Health Organisation: Treatment of Mycobacterium ulcerans disease (Buruli ulcer): guidance for health workers. Geneva, Switzerland; 2012.
• [5]Johnson PD, Hayman JA, Quek TY, Fyfe JA, Jenkin GA, Buntine JA, Athan E, Birrell M, Graham J, Lavender CJ: Consensus recommendations for the diagnosis, treatment and control of mycobacterium ulcerans infection (Bairnsdale or Buruli ulcer) in Victoria, Australia. The Medical journal of Australia 2007, 186(2):64-68.
• [6]O'Brien DP, Robson ME, Callan PP, McDonald AH: "Paradoxical" immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure. The Medical journal of Australia 2009, 191(10):564-566.
• [7]Ruf MT, Chauty A, Adeye A, Ardant MF, Koussemou H, Johnson RC, Pluschke G: Secondary Buruli ulcer skin lesions emerging several months after completion of chemotherapy: paradoxical reaction or evidence for immune protection? PLoS neglected tropical diseases 2011, 5(8):e1252.
• [8]Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, Awuah PC, Awuah-Boateng NY, Adjei O, Bretzel G, Schouten JP, et al.: Paradoxical responses after start of antimicrobial treatment in mycobacterium ulcerans infection. Clin Infect Dis 2012, 54(4):519-526.
• [9]Sarfo FS, Phillips R, Asiedu K, Ampadu E, Bobi N, Adentwe E, Lartey A, Tetteh I, Wansbrough-Jones M: Clinical efficacy of combination of rifampin and streptomycin for treatment of mycobacterium ulcerans disease. Antimicrobial agents and chemotherapy 2010, 54(9):3678-3685.
• [10]Phillips R, Sarfo FS, Guenin-Mace L, Decalf J, Wansbrough-Jones M, Albert ML, Demangel C: Immunosuppressive signature of cutaneous mycobacterium ulcerans infection in the peripheral blood of patients with buruli ulcer disease. The Journal of infectious diseases 2009, 200(11):1675-1684.
• [11]Torrado E, Fraga AG, Logarinho E, Martins TG, Carmona JA, Gama JB, Carvalho MA, Proenca F, Castro AG, Pedrosa J: IFN-gamma-dependent activation of macrophages during experimental infections by mycobacterium ulcerans is impaired by the toxin mycolactone. Journal of immunology 2010, 184(2):947-955.
• [12]Boulkroun S, Guenin-Mace L, Thoulouze MI, Monot M, Merckx A, Langsley G, Bismuth G, Di Bartolo V, Demangel C: Mycolactone suppresses T cell responsiveness by altering both early signaling and posttranslational events. Journal of immunology 2010, 184(3):1436-1444.
• [13]Sarfo FS, Phillips RO, Ampadu E, Sarpong F, Adentwe E, Wansbrough-Jones M: Dynamics of the cytokine response to mycobacterium ulcerans during antibiotic treatment for M. ulcerans disease (Buruli ulcer) in humans. Clinical and vaccine immunology: CVI 2009, 16(1):61-65.
• [14]Schutte D, Pluschke G: Immunosuppression and treatment-associated inflammatory response in patients with mycobacterium ulcerans infection (Buruli ulcer). Expert opinion on biological therapy 2009, 9(2):187-200.
• [15]Schutte D, Umboock A, Pluschke G: Phagocytosis of mycobacterium ulcerans in the course of rifampicin and streptomycin chemotherapy in Buruli ulcer lesions. The British journal of dermatology 2009, 160(2):273-283.
• [16]O'Brien DP, Hughes AJ, Cheng AC, Henry MJ, Callan P, McDonald A, Holten I, Birrell M, Sowerby JM, Johnson PD, et al.: Outcomes for mycobacterium ulcerans infection with combined surgery and antibiotic therapy: findings from a south-eastern Australian case series. The Medical journal of Australia 2007, 186(2):58-61.
• [17]Friedman ND, McDonald A, Robson M, O'Brien DP: Corticosteroid use for paradoxical reactions during antibiotic treatment for mycobacterium ulcerans. PLoS neglected tropical diseases 2012, 6(9):e1767.
• [18]Lawn SD, Meintjes G: Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy. Expert review of anti-infective therapy 2011, 9(4):415-430.
• [19]O'Brien DP, McDonald A, Callan P, Robson M, Friedman ND, Hughes A, Holten I, Walton A, Athan E: Successful outcomes with oral fluoroquinolones combined with rifampicin in the treatment of mycobacterium ulcerans: an observational cohort study. PLoS neglected tropical diseases 2012, 6(1):e1473.
• [20]van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K: Mycobacterium ulcerans infection. Lancet 1999, 354(9183):1013-1018.
• [21]Sizaire V, Nackers F, Comte E, Portaels F: Mycobacterium ulcerans infection: control, diagnosis, and treatment. The Lancet infectious diseases 2006, 6(5):288-296.
• [22]Pak J, O'Brien DP, Quek TY, Athan E: Treatment costs of mycobacterium ulcerans in the antibiotic era. International Health 2012, 4(2):123-127.
• [23]Gooding TM, Johnson PD, Campbell DE, Hayman JA, Hartland EL, Kemp AS, Robins-Browne RM: Immune response to infection with mycobacterium ulcerans. Infection and immunity 2001, 69(3):1704-1707.
• [24]Portaels F, Silva MT, Meyers WM: Buruli ulcer. Clinics in dermatology 2009, 27(3):291-305.
• [25]Breton G, Duval X, Estellat C, Poaletti X, Bonnet D, Mvondo Mvondo D, Longuet P, Leport C, Vilde JL: Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004, 39(11):1709-1712.
• [26]Ji B, Lefrancois S, Robert J, Chauffour A, Truffot C, Jarlier V: In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against mycobacterium ulcerans. Antimicrobial agents and chemotherapy 2006, 50(6):1921-1926.
• [27]Amsden GW: Anti-inflammatory effects of macrolides–an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? The Journal of antimicrobial chemotherapy 2005, 55(1):10-21.
• [28]Dalhoff A: Immunomodulatory activities of fluoroquinolones. Infection 2005, 33(Suppl 2):55-70.
• [29]Chauty A, Ardant MF, Marsollier L, Pluschke G, Landier J, Adeye A, Goundote A, Cottin J, Ladikpo T, Ruf T, et al.: Oral treatment for mycobacterium ulcerans infection: results from a pilot study in Benin. Clin Infect Dis 2011, 52(1):94-96.