Vet Dermatol 2015
DOI: 10.1111/vde.12210
Deep pyoderma caused by Burkholderia cepacia complex associated with ciclosporin administration in dogs: a case series Frane Banovic*†, Sandra Koch‡, David Robson§, Megan Jacob¶ and Thierry Olivry*† *Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC, 27607, USA †Center for Comparative Medicine and Translational Research, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA ‡Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Ave, C339 VMC, St Paul, MN, 55108, USA §Animal Skin and Allergy Service, Melbourne Veterinary Specialist Centre, 70 Blackburn Road, Glen Waverley, VIC, 3150, Australia ¶Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC, 27607, USA Correspondence: Thierry Olivry, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC 27607, USA. E-mail: [email protected]
Background – Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous Gram-negative bacilli associated with fatal nosocomial infections in humans; multi-antibiotic resistance makes this organism a serious threat in hospital settings. Objective – To describe the historical, clinicopathological and treatment characteristics of Bcc-associated deep skin infections in dogs. Animals – Six dogs with skin infections in which skin bacterial cultures resulted in pure growth of Bcc. Methods – Retrospective study with review of medical records and skin biopsies. Results – All dogs were receiving oral ciclosporin at the time of skin infection development. All dogs were castrated males and four of six were West Highland white terriers. Cutaneous lesions consistent with deep pyoderma were confined mainly to the trunk. In all dogs skin cytology revealed a strong inflammatory response, with moderate to abundant numbers of intracellular (neutrophils and macrophages) and extracellular bacilli. In three dogs histopathology showed a multifocal, nodular to coalescing pyogranulomatous dermatitis associated with multifocal folliculitis and furunculosis. Tissue Giemsa and Gram stains identified numerous Gram-negative rods within macrophages. Antimicrobial susceptibility testing revealed multidrug-resistant Bcc strains with sensitivity to trimethoprim/sulfonamides in all dogs and to marbofloxacin, piperacillin and ceftazidime in three dogs. Successful treatment was achieved in all dogs using trimethoprim/sulfonamides or quinolones (marbofloxacin, ciprofloxacin) or doxycycline in conjunction with ciclosporin withdrawal. Conclusions and clinical importance – Clinicians should be aware of the rare potential for Bcc-associated deep skin infections in dogs receiving oral ciclosporin. Owners should be made conscious of the potential transmission risk to humans or other animals.
Introduction The Burkholderia cepacia complex (Bcc), formerly Pseudomonas cepacia, represents a group of phenotypically similar, but genetically distinct, motile, aerobic, glucosenonfermenting Gram-negative bacilli.1 These bacteria are widely distributed in the natural environment and can be isolated from water, soil, fruits and vegetables.1 Burkholderia organisms rarely cause infections in immunocompetent hosts, but Bcc has emerged as an important opportunistic pathogen in hospitalized (i.e. nosocomial infection) and immunocompromised patients.2
Accepted 23 February 2015 Sources of Funding: This study was self-funded. Conflict of Interest: No conflicts of interest have been declared. © 2015 ESVD and ACVD, Veterinary Dermatology
This report describes the historical, clinicopathological and treatment characteristics of Bcc deep skin infections in six dogs treated with ciclosporin orally.
Case reports Electronic medical records were searched at three institutions for skin bacterial culture results having yielded pure growth of Bcc organisms between the periods of 1999 (institution 1), 2005 (institution 2), 2008 (institution 3) and 2014; six dogs met this criterion and were included in this report. Signalment and history Signalment and historical data on the six dogs are summarized in Table 1. All dogs were castrated males and four of six were West Highland white terriers. All dogs had a previous history of a skin disease (four 1
Banovic et al.
Table 1. Signalment and historical features of six dogs with Burkholderia cepacia complex pyoderma Treatments for skin disease and duration before the diagnosis of B. cepacia complex pyoderma (days)
Age (years)
Sex
Weight (kg)
Prior skin disease
6.5
MC
39
Sebaceous adenitis
Dog
Breed
Case 1
Old English sheepdog
Case 2
West Highland white terrier
11
MC
9.7
Atopic dermatitis
Case 3
West Highland white terrier
3
MC
6.7
Atopic dermatitis
Case 4
West Highland white terrier
3.2
MC
10.3
Atopic dermatitis
Case 5
Dachshund
2.5
MC
7.7
Case 6
West Highland white terrier
1.8
MC
12
Sebaceous adenitis Atopic dermatitis
Ciclosporin 5.1 mg/kg once daily, ketoconazole 5.1 mg/kg once daily (90 days) Ciclosporin 5.1 mg/kg once daily (45 days) Ciclosporin 7.4 mg/kg every other day (320 days) Ciclosporin 4.8 mg/kg once daily 5 days/week, ketoconazole 4.8 mg/kg once daily 2 days/week (65 days) Ciclosporin 4.8 mg/kg once daily, vitamin A (8000 IU) once daily, x3 fatty acids once daily (345 days) Ciclosporin 5 mg/kg once daily, prednisone 0.4 mg/kg every other day (34 days)
Prior noncutaneous disease None
Diabetes mellitus Diabetes mellitus None
None
None
Abbreviation: MC, male castrated.
atopic dermatitis and two sebaceous adenitis) that was managed with ciclosporin (range 4.8–7.4 mg/kg, mean 5.3 mg/kg), in conjunction with ketoconazole in two dogs. Four of six dogs developed skin lesions within 3 months of starting ciclosporin, the other two after 8 months. The owners reported the acute dissemination from initial single lesions to multiple in a diffuse pattern. In dog 3, which suffered from diabetic ketoacidosis at presentation, skin lesions developed immediately after dorsal placement of a glucose-monitoring system device. An association with other predisposing factors could not be found for the other dogs apart from diabetes mellitus (dog 2) and immunomodulating therapy. An extracutaneous spread of Bcc bacteria was not reported for any dogs; blood cultures were not performed, however. Dermatological examination Lesions of Bcc infection seemed restricted to the skin. In all dogs, cutaneous lesions were confined to the trunk and upper limbs. These lesions consisted of multifocal irregular, erythematous to haemorrhagic alopecic papules, plaques and nodules, with extensive crusting, draining tracts and ulceration (Figure 1). In dog 3 (Figure 1c), lesions on the dorsum clustered into a severe diffuse linear cellulitis. Some lesions appeared as punched-out deep ulcers (Figure 1a,b). Lesions were mildly to severely painful on palpation in all patients. All dogs exhibited peripheral lymphadenopathy, while three dogs were hyperthermic and inappetent. Cytological findings Skin cytology in all dogs revealed a marked inflammatory response consisting of nondegenerative and degenerative neutrophils and macrophages, with moderate to abundant numbers of intracellular (neutrophils and macrophages) and extracellular rods. Few cocci in neutrophils were additionally seen in two dogs (dogs 2 and 5). 2
Bacterial culture and susceptibility testing Three different veterinary diagnostic laboratories identified Bcc organisms and determined antimicrobial susceptibility and interpretations (susceptible, intermediate and resistant) following Clinical and Laboratory Standards Institute guidelines. Pure cultures of Bcc bacteria were isolated from skin lesions in all dogs. The degree of bacterial growth was described as light (dog 5), moderate (dogs 1 and 2) or heavy (dogs 3, 4 and 6). Antibiotics to which isolates were reported resistant by the broth microdilution method included amikacin, amoxicillin/clavulanic acid, cefalexin, cefpodoxime, ceftiofur, cefovecin, chloramphenicol, gentamicin and tobramycin in all six dogs and tetracycline and enrofloxacin in five of the six dogs. Antibiotics to which isolates were reported to be sensitive included trimethoprim/sulfonamides in all dogs and marbofloxacin, piperacillin and ceftazidime in three of the six dogs (Table 2). Dermatopathology Microscopic examination of skin samples acquired via a punch biopsy from three dogs (dogs 1, 4 and 5) revealed similar changes: these consisted of multifocal, nodular to coalescing pyogranulomatous dermatitis attributed to multifocal folliculitis and furunculosis (Figure 2a,b). In all dogs, the inflammation extended to the panniculus. Varying degrees of epidermal hyperplasia, with several intrafollicular to subcorneal pustules (dog 1) and ulcerative dermatitis (all dogs) were noted. Tissue Giemsa and Gram stains identified numerous Gram-negative rods within macrophages and free in the dermis and panniculus (Figure 2b,c). Treatment approach and outcome Complete resolution of skin lesions in all dogs was obtained with appropriate therapy continued for up to 3 weeks beyond clinical resolution (Table 2). Dogs receiving trimethoprim/sulfonamides developed expected adverse effects, such as anaemia, clinical hypothyroidism © 2015 ESVD and ACVD, Veterinary Dermatology
Burkholderia cepacia pyoderma in dogs
a
b
c
d
Figure 1. (a) Multifocal deep erythematous to haemorrhagic ulcers with punched-out appearance after crust removal on the thorax of dog 5. (b and inset) Multifocal proliferative to ulcerated papules and crusted plaques in dog 1 with sebaceous adenitis. (c) Diffuse linear proliferative erythematous plaques with serosanguinous exudate on the mid-dorsum in dog 3. (d) Resolution of the same lesion from dog 3 (c) with scarring and alopecia. Table 2. Treatment approach and outcome in six dogs with B. cepacia pyoderma Systemic antibacterial therapy
Dog
Antimicrobial sensitivity
Immunomodulatory drugs after diagnosis
Before diagnosis (duration)
After diagnosis (duration until CR)
Case 1
Ceftazidime, piperacillin, TMS
Discontinued after 1 week
Cefalexin 25.6 mg/kg twice daily (2 weeks)
CR
Case 2
Ciprofloxacin, marbofloxacin, piperacillin, TMS Ciprofloxacin, marbofloxacin, piperacillin, TMS Ceftazidime, tetracycline, TMS
Continued without any changes Discontinued immediately Discontinued immediately
Case 5
Enrofloxacin, marbofloxacin, TMS
Discontinued ciclosporin after 6 weeks; prednisone 1.9 mg/kg once daily for 2 weeks, then tapered
Clindamycin 15.4 mg/kg twice daily (7 days) Enrofloxacin 10.1 mg/kg once daily (30 days) Enrofloxacin 4.8 mg/kg once daily, clindamycin 7.2 mg/kg twice daily (both 4 weeks) Cefpodoxime 6.4 mg/kg once daily (5 days)
TMS 36 mg/kg twice daily (2 weeks), rifampin 3.8 mg/kg twice daily (33 days), clindamycin 11.5 mg/kg twice daily (19 days) Ciprofloxacin 25.7 mg/kg once daily (8 weeks) Marbofloxacin 5.5 mg/kg once daily (12 weeks) Doxycyline 4.8 mg/kg once daily (6 weeks)
CR
Case 6
TMS
Discontinued immediately
Marbofloxacin 3.2 mg/kg once daily (4 weeks), then enrofloxacin 4.4 mg/kg once daily (2 weeks), then enrofloxacin 8.8 mg/kg once daily (12 weeks) and TMS 31.1 mg/kg twice daily (4 weeks) TMS 20 mg/kg twice daily (8 weeks)
Case 3 Case 4
Clindamycin 12.5 mg/kg once daily, enrofloxacin 6.2 mg/kg once daily (2 weeks)
Outcome
CR CR CR
CR
Abbreviations: CR, complete remission; TMS, trimethoprim/sulfonamide.
(dog 5) and keratoconjunctivitis sicca (dog 1). In dog 5, episodes of trembling, agitation and restlessness were noted after marbofloxacin administration. Five dogs © 2015 ESVD and ACVD, Veterinary Dermatology
received topical baths twice weekly with a chlorhexidine medicated shampoo. Topical mupirocin ointment (dog 1) and 1% silver sulfadiazine cream (dog 6) were applied 3
Banovic et al.
a
b
c
Figure 2. (a) Severe folliculitis and furunculosis with pyogranulomatous inflammation in dog 4. Haematoxylin and eosin; 95 magnification. (b) Higher magnification of (a; white inset). Numerous free rod-shaped bacteria (arrows) in the hair follicle wall. Giemsa; 960 magnification. (c) Higher magnification of (a; black inset). Numerous intracellular rod-shaped bacteria are seen in macrophages. Giemsa; 960 magnification.
twice daily until complete skin resolution. Immunomodulating drugs were eventually discontinued in all dogs except for dog 2. After 6 weeks, clinical improvement in dog 5 was mild, and subsequent blood monitoring revealed a ciclosporin trough level of 102 ng/mL. Ciclosporin was then discontinued, with moderate clinical improvement reported in the following 2 weeks. After complete resolution, ciclosporin was restarted only in dog 1 (5 mg/kg, once daily without ketoconazole); a recurrence of Bcc-associated skin lesions was not reported in any dogs over several years of follow-up. The long-term management of atopic dogs consisted of weekly topical antiseptic shampoo and glucocorticoid therapy, intermittent short courses of oral glucocorticoids and immunotherapy, while dog 5, with sebaceous adenitis, achieved moderate improvement with oral vitamin A and topical twice weekly baby oil soaks and antiseborrhoeic shampoo.
Discussion There are only rare reports of Bcc cutaneous infection in veterinary medicine; these include subclinical mastitis in a large flock of dairy sheep and cutaneous abscesses in an emaciated ewe.3,4 Previous descriptions of Bcc-associated skin infections in small animals were not identified. In this report, all dogs exhibited deep pyoderma with an acute evolution, which was associated with cellulitis in 4
some patients. Unlike acute Pseudomonas aeruginosaassociated pyoderma in dogs,5 the skin lesions of Bcc infection were widespread and, although painful, did not require sedation for diagnostic work-up. Interestingly, male castrated West Highland white terriers seemed over-represented, but a specific breed predisposition could not be evaluated because of the multicentre retrospective nature of this report and the lack of a reference population. Invasive Bcc infections, such as fatal necrotizing pneumonia and septicaemia, have been shown to occur in humans with the immunodeficiency associated with cystic fibrosis and chronic granulomatous disease.6,7 In humans, ciclosporin therapy, diabetes mellitus and Bcc bacteraemia are known to predispose to deep Bcc skin infections.8,9 While two of the dogs in this report had suffered from diabetes mellitus, all six dogs received oral ciclosporin at varying dosages and duration; two dogs also received concurrent ketoconazole for ciclosporin dosereduction purposes.10,11 High ciclosporin levels have been suspected to lead to the development of cutaneous nocardiosis in a dog.12 In this case series, a trough ciclosporin blood concentration was measured in only one dog, and it was lower than that needed for immunosuppression for organ transplantation in dogs (i.e. a range of 400–600 ng/mL).13 Measurement of ciclosporin trough concentrations in future cases of suspected ciclosporinassociated opportunistic infections may assist in clarifying © 2015 ESVD and ACVD, Veterinary Dermatology
Burkholderia cepacia pyoderma in dogs
the role of high ciclosporin levels for development of these rare events. Unlike other opportunistic pathogens, Bcc bacteria are not normally carried as commensal organisms on human or canine skin.14,15 As a result, the organisms are acquired either nosocomially or from the environment. While Bcc have useful commercial properties in agriculture as biocontrol agents and biopesticides, nosocomial outbreaks have been associated with contaminated disinfectants, hospital tap water, intravenous solutions, human transmission and medical devices.16–20 In companion animal veterinary practices, the demonstration of an environmental presence of Bcc has been limited to two reports revealing the contamination of surgical cold sterile solutions and of commercial ear-cleaner solutions.21,22 Although Bcc have been implicated in otitis media in mice, Bcc have not been reported as a causative agent of otitis in companion animals, to the authors’ knowledge.23 In this report, even though the owners implicated a causal association of Bcc pyoderma with a medical device placement in one dog, antiseptic solution or medical device contamination was not confirmed using bacterial cultures. Like P. aeruginosa, Bcc species have several antimicrobial protection mechanisms that, under antimicrobial pressure, could confer resistance to several classes of antibiotics, such as aminoglycosides, b-lactams, trimethoprim/sulfonamides, chloramphenicol and quinolones.24 In a retrospective antimicrobial susceptibility analysis of 50 Bcc isolated from ear, nasopharynx, uterus, urine and bronchoalveolar lavages of small animals, a susceptibility to trimethoprim/sulfonamides, imipenem and cefquinome was most common.25 In this report, Bcc strains were found to be sensitive to trimethoprim/sulfonamides (all dogs), followed by marbofloxacin, piperacillin and ceftazidime (three dogs). In humans with cystic fibrosis and chronic granulomatous disease, recommendations for pulmonary Bcc treatment include the use of intravenous meropenem plus one of the following: ceftazidime, chloramphenicol, trimethoprim/sulfonamides or aztreonam.26 In this report, successful treatment of Bcc skin infections was achieved using trimethoprim/sulfonamides, quinolones (marbofloxacin, ciprofloxacin) or doxycycline. In conclusion, this report represents, to the best of the authors’ knowledge, the first description of successfully treated Bcc-associated deep pyoderma in dogs. While all the dogs of this report were receiving ciclosporin immunomodulation, it is likely that Bcc pyodermas associated with other immunodeficient states also exist.
Acknowledgments We would like to thank Maarja Uri for providing us with clinical photographs.
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5.
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References 23. €bel UB. Stenotrophomonas maltophilia and 1. Maschmeyer G, Go Burkholderia cepacia. In: Mandell GA, Bennett JE, Dolin R, Gerald L, eds. Principles and Practice of Infectious Diseases. 6th
© 2015 ESVD and ACVD, Veterinary Dermatology
edition. Philadelphia, PA, USA: Churchill Livingstone, 2005; 2615–2622. Huang CH, Jang TN, Liu CY et al. Characteristics of patients with Burkholderia cepacia bacteremia. J Microbiol Immunol Infect 2001; 34: 215–219. Berriatua E, Ziluaga I, Miguel-Virto C et al. Outbreak of subclinical mastitis in a flock of dairy sheep associated with Burkholderia cepacia complex infection. J Clin Microbiol 2001; 39: 990–994. Al Dughaym AM. Isolation of Serratia, Arcanobacterium and Burkholderia species from visceral and cutaneous abscesses in four emaciated ewes. Vet Rec 2004; 155: 425–426. Hillier A, Alcorn JR, Cole LK et al. Pyoderma caused by Pseudomonas aeruginosa infection in dogs: 20 cases. Vet Dermatol 2006; 17: 432–439. Drevinek P, Mahenthiralingam E. Burkholderia cenocepacia in cystic fibrosis: epidemiology and molecular mechanisms of virulence. Clin Microbiol Infect 2010; 16: 821–830. Winkelstein JA, Marino MC, Johnston RB Jr et al. Chronic granulomatous disease: report on a national registry of 368 patients. Medicine 2000; 79: 155–169. €zeri B et al. Soft tissue infection caused by Yıldız B, Duyu M, So Burkholderia cepacia in a child with polyarteritis nodosa. Turk J Pediatr 2012; 54: 664–666. Fadini GP, Tiengo A, Avogaro A. First isolation of Burkholderia cepacia from a deep neck abscess in a diabetic patient successfully treated with hyperbaric oxygen. J Clin Microbiol 2005; 43: 529. Dahlinger J, Gregory C, Bea J. Effect of ketoconazole on cyclosporine dose in healthy dogs. Vet Surg 1998; 27: 64–68. Gray LL, Hillier A, Cole LK et al. The effect of ketoconazole on whole blood and skin ciclosporin concentrations in dogs. Vet Dermatol 2013; 24: 118–125. Siak MK, Burrows AK. Cutaneous nocardiosis in two dogs receiving ciclosporin therapy for the management of canine atopic dermatitis. Vet Dermatol 2013; 24: 453–456. Mathews KA, Holmberg DL, Miller CW. Kidney transplantation in dogs with naturally occurring end-stage renal disease. J Am Anim Hosp Assoc 2000; 36: 294–301. Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol 2011; 9: 244–253. Rodrigues Hoffmann A, Patterson AP, Diesel A et al. The skin microbiome in healthy and allergic dogs. PLoS ONE 2014; 9: e83197. Holmes A, Govan J, Goldstein R. Agricultural use of Burkholderia (Pseudomonas) cepacia: a threat to human health? Emerg Infect Dis 1998; 4: 221–227. Hutchinson GR, Parker S, Pryor JA et al. Home-use nebulizers: a potential primary source of Burkholderia cepacia and other colistin-resistant, Gram-negative bacteria in patients with cystic fibrosis. J Clin Microbiol 1996; 34: 584–587. Oie S, Kamiya A. Microbial contamination of antiseptics and disinfectants. Am J Infect Control 1996; 24: 389–395. Fung SK, Dick H, Devlin H et al. Transmissibility and infection control implications of Burkholderia cepacia in cystic fibrosis. Can Infect Dis J 1998; 9: 177–182. Nasser RM, Rahi AC, Haddad MF et al. Outbreak of Burkholderia cepacia bacteremia traced to contaminated hospital water used for dilution of an alcohol skin antiseptic. Infect Control Hosp Epidemiol 2004; 25: 231–239. Murphy CP, Weese JS, Reid-Smith RJ et al. The prevalence of bacterial contamination of surgical cold sterile solutions from community companion animal veterinary practices in southern Ontario. Can Vet J 2010; 51: 634–636. Bartlett SJ, Rosenkrantz WS, Sanchez S. Bacterial contamination of commercial ear cleaners following routine home use. Vet Dermatol 2011; 22: 546–553. Hobson R, Gould I, Govan J. Burkholderia (Pseudomonas) cepacia as a cause of brain abscesses secondary to chronic suppurative otitis media. Eur J Clin Microbiol Infect Dis 1995; 14: 908– 911.
5
Banovic et al.
24. Hancock RE. Resistance mechanisms in Pseudomonas aeruginosa and other nonfermentative gram-negative bacteria. Clin Infect Dis 1998; 27: 93–99. 25. Attili AR, Tambella AM, Preziuso S et al. Burkholderia cepacia complex in clinically-infected animals: retrospective analysis, antibiotic resistance, and potential hazard for public health. In Proceedings of the 23rd European Society of Clinical Microbiol-
ogy and Infectious Diseases, 2013; 1450 (Abstract). Available at: https://www.escmid.org/escmid_library/online_lecture_library/ material/?mid=7107. Accessed Mar 1, 2015. 26. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–951.
sume Re ries du complexe Burkholderia cepacia (Bcc) sont des bacilles ram ne gatives ubiquiContexte – Les bacte es a des infectons nosocomiales mortelles chez l’homme; des re sistances multiples aux antitaires associe rieuse dans le milieu hospitalier. biotiques font de ces organismes une menace se crire les caracte ristiques anamnestiques, clinicopathologiques et the rapeutiques des infecObjectif – De tions profondes a Bcc chez le chien. sentant une infection cutane e avec une culture bacte riologique de Bcc pure. Sujets – Six chiens pre thodes – Etude re trospective avec revue des donne es me dicales et des biopsies cutane es. Me sultats – Tous les chiens recevaient de la ciclosporine orale au moment du de veloppement de l’infection Re e. Tous les chiens e taient des m^ales castre s et quatre sur six e taient des West Highland white terricutane sions cutane es consistaient en une pyodermite profonde principalement localise e au tronc. Pour ers. Les le e re ve lait une intense re ponse inflammatoire avec un nombre mode re tous les chiens une cytologie cutane a important de bacilles intracellulaires (neutrophiles et macrophages) et extracellulaires. Pour trois chiens, ve lait une dermatite pyogranulomateuse multifocale, nodulaire e l’histopathologie re a coalescente associe a une folliculite et furonculose multifocale. Les colorations Giemsa et Gram re ve laient de nombreux b^ atongatifs au sein de macrophages. L’antibiogramme re ve laient des souches de Bcc multire sisnets Gram ne toprimes/sulfamide s chez tous les chiens et pour trois chiens tantes sensible a aux trime a la te re alise pour tous les chiens avec marbofloxacine, piperacilline et ceftazidime. Un traitement efficace a e ^t trimethoprime/sulfonamides ou quinolones (marbofloxacine, ciprofloxacine) ou doxycycline associe a l’arre de la ciclosporine. Conclusions et importance clinique – Les cliniciens doivent suspecter le rare potentiel des infections es profondes lie es a Bcc chez les chiens recevant de la ciclosporine orale. Les proprie taires doivent cutane ^tre avertis du risque de transmission a l’homme et aux autres animaux. e Resumen n – las bacterias del complejo Burkholdera cepacia (Bcc) son bacilos Gram negativos ubicuos Introduccio ticos mu ltiples hace asociados con infecciones nosocomiales fatales en humanos; la resistencia a antibio de este organismo un riesgo muy serio en hospitales. ricas, clınico-patolo gicas y el tratamiento de infecciones profunObjetivo – describir las caracterısticas histo das de la piel de perros asociados con Bcc. Animales – seis perros con infecciones de la piel con cultivo puro de Bcc. todos – estudio retrospectivo con revisio n de los historiales clınicos y biopsias de piel Me Resultados – todos los perros estaban recibiendo ciclosporina oral en el momento del desarrollo de la inn de la piel. Todos los perros eran machos castrados y cuatro de ellos eran de la raza West Highland feccio White Terrier. Las lesiones cutaneas consistieron en pioderma profunda restringida fundamentalmente a la una respuesta inflamatoria intensa con zona del tronco. En todos los perros la citologıa de la piel revelo filos y macro fagos) y extracelulares. meros moderados a abundantes de bacilos intracelulares (en neutro nu una dermatitis multifocal, nodular a confluente piogranulomaEn tres de los perros la histopatologıa mostro tosa asociada con foliculitis multifocal y furunculosis. Las tinciones de Giemsa y Gram para tejidos identififagos. Las pruebas de susceptibilidad caron numerosos bacilos Gram negativos dentro de macro ltiple a los f antimicrobiana revelaron cepas de Bcc con resistencia mu armacos y sensibilidad a trimetoprima/sulfonamida en todos los perros y a marbofloxacina, piperacilina y ceftazidima en tres perros. Se obtuvo un tratamiento eficaz en todos los perros utilizando trimetoprima/sulfonamida o quinolonas (marbofloxacina, ciprofloxacina) o doxiciclina conjuntamente con la retirada del tratamiento de ciclosporina Conclusiones e importancia clınica – los clınicos deben conocer el raro potencial de desarrollar infecciones profundas de la piel producidas por Bcc en perros recibiendo ciclosporina oral. Los propietarios deben n a humanos y a otros animales. ser conscientes del potencial de transmisio Zusammenfassung Hintergrund – Bakterien des Burkholderia cepacia Komplexes (Bcc) sind ubiquit€ are Gram-negative Bazil€dlichen nosokomialen Infektionen des Menschen auftreten; die multiple Resistenz gegen Anlen, die bei to tibiotika macht diesen Organismus zu einer gef€ ahrlichen Bedrohung in Krankenh€ ausern. Ziel – Eine Beschreibung der Anamnese, der klinischen Pathologie und der Behandlungscharakteristika die mit Bcc auftretenden tiefen Hautinfektionen bei Hunden. 6
© 2015 ESVD and ACVD, Veterinary Dermatology
Burkholderia cepacia pyoderma in dogs
Tiere – Sechs Hunde mit Hautinfektionen, bei denen die Bakterienkulturen ein reines Wachstum von Bcc ergaben. Methoden – Es handelt sich um eine retrospektive Studie mit einer Review der medizinischen Patientendaten und der Hautbiopsien. Ergebnisse – Alle Hunde erhielten zum Zeitpunkt der Entstehung der Hautinfektion Ciclosporin per os. Alle €den und vier waren West Highland White Terrier. Die Hautver€ Hunde waren kastrierte Ru anderungen entsprachen einer tiefen Pyodermie und waren haupts€ achlich auf den Rumpf beschr€ ankt. Bei allen Hunden ze€ndliche Reaktion, mit moderaten bis zahlreichen intrazellul€ igte die Zytologie eine starke entzu aren (Neutrophile und Makrophagen) und extrazellul€ aren Bazillen. Bei drei Hunden zeigte die Histopathologie €se Dermatitis, die gemeinsam mit einer multieine multifokale, knotige bis koaleszierende pyogranulomato fokalen Follikulitis und Furunkulose auftrat. Giemsa und Gramf€ arbungen der Gewebe ergaben zahlreiche Gram-negative St€abchen in den Makrophagen. Eine Bakterienkultur mit Antibiogramm ergab einen multiresistenten Bcc Stamm mit einer Sensibilit€ at auf Trimethoprim/Sulfonamide bei allen Hunden und auf Marbofloxacin, Piperacillin und Ceftazidime bei drei Hunden. Eine erfolgreiche Behandlung wurde bei allen Hunden mit Trimethoprim/Sulfonamide oder Quinolonen (Marbofloxacin, Ciprofloxacin) oder Doxycyclin in Verbindung mit einem Absetzen von Ciclosporin erzielt. Schlussfolgerungen und klinische Bedeutung – KlinikerInnen sollten sich bewusst sein, dass tiefe Haut€nnen. Die BesitzerIninfektionen durch Bcc bei Hunden, denen Ciclosporin verabreicht wird, auftreten ko € €gliche Ubertragungsrisiken €ber mo nen sollten u auf Menschen oder andere Tiere aufmerksam gemacht werden. 摘要 背景 – 洋葱伯克霍尔德菌复合物(Bcc)细菌无处不在,是引起人严重感染的革兰氏阴性杆菌;多重抗生素耐药 性使得其极难治疗。 目的 – 描述犬Bcc导致皮肤感染的病史、临床发病机理和治疗特点。 动物 – 六只皮肤感染的犬,皮肤细菌培养结果为纯Bcc增殖。 方法 – 回顾性研究诊疗纪录和皮肤活检结果。 结果 – 所有犬在皮肤感染时期均口服环孢素。所有犬为去势公犬,六只中的四只为西高地白㹴。皮肤病变属 于深度脓皮病,主要集中在躯干部。所有犬的细胞学显示严重的炎症反应,伴有中度的细胞内(中性粒细胞和 巨噬细胞)及细胞外杆菌。三只犬的组织病理学显示为多病灶、结节性聚集的脓性肉芽肿性皮炎,多病灶性毛 囊炎及疖病。组织姬姆萨和革兰氏染色显示巨噬细胞内有许多革兰氏阴性杆菌。药敏试验显示Bcc菌株多重 耐药性,所有犬甲氧苄氨嘧啶/磺胺类敏感,三只犬马坡沙星、派拉西林和头孢他啶敏感。所有犬使用甲氧苄 氨嘧啶/磺胺类,或喹诺酮类(马波沙星、环丙沙星),或配合多西环素,同时停用环孢素治疗成功。 总结与临床意义 – 临床医生应了解,尽管罕见,使用环孢素的犬有Bcc导致深度皮肤感染的可能。主人应意识 到有传染给人类或其他动物的潜在风险。 要約 背景 – Burkholderia cepacia複合体(Bcc)の細菌はいたるところに存在する、ヒトで致命的な院内感染に関連する グラム陰性桿菌であり、複数の抗菌剤耐性によりこの微生物が病院内の環境において深刻な脅威となっている。 目的 – イヌにおけるBcc関連性深在性皮膚感染症の歴史、臨床病理、治療の特徴を解説すること。 供与動物 – Bccの純粋増殖が皮膚細菌培養検査の結果として得られた、皮膚感染のある6頭のイヌ。 方法 – 診療記録と皮膚生検の再検討による回顧的研究 結果 – すべてのイヌが皮膚感染発生時に経口シクロスポリンを投与されていた。すべてのイヌは去勢雄で、6頭中4頭 がウエストハイランドホワイトテリアであった。皮膚病変は深在性膿皮症と一致し、主に体幹部に限定して認められた。す べてのイヌの皮膚細胞診において、中程度から豊富な数の細胞内(好中球およびマクロファージ)および細胞外桿菌を 伴う、強い炎症性反応が明らかになった。3頭のイヌでは病理組織は多病巣性の毛包炎やフルンケローシスを伴う、 多病巣性で結節性から癒合性の化膿性肉芽腫性皮膚炎を示していた。組織のギムザ染色およびグラム染色は多数 のグラム陰性桿菌をマクロファージ内に特定した。抗菌剤感受性試験はトリメトプリム/スルフォンアミドに感受性の多剤 耐性Bcc株をすべてのイヌで、マルボフロキサシン、ピペラシン、セフタジジムに感受性の多剤耐性Bcc株を3頭のイヌ で明らかにした。すべてのイヌにおいて、トリメトプリム/スルフォンアミドあるいはキノロン(マルボフロキサシン、シプロフロキサ シン)、あるいはドキシサイクリンの使用とシクロスポリンの休薬とともに治療が成功した。 結論および臨床的な重要性 – 臨床家は経口シクロスポリン投与をしているイヌにおいてBcc関連性深在性皮膚感染症 の稀な可能性に注意すべきである。飼い主はヒトや他の動物に対する潜在的な伝染のリスクを意識するべきである。
© 2015 ESVD and ACVD, Veterinary Dermatology
7
DOI: 10.1111/vde.12210
Deep pyoderma caused by Burkholderia cepacia complex associated with ciclosporin administration in dogs: a case series Frane Banovic*†, Sandra Koch‡, David Robson§, Megan Jacob¶ and Thierry Olivry*† *Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC, 27607, USA †Center for Comparative Medicine and Translational Research, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA ‡Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Ave, C339 VMC, St Paul, MN, 55108, USA §Animal Skin and Allergy Service, Melbourne Veterinary Specialist Centre, 70 Blackburn Road, Glen Waverley, VIC, 3150, Australia ¶Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC, 27607, USA Correspondence: Thierry Olivry, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC 27607, USA. E-mail: [email protected]
Background – Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous Gram-negative bacilli associated with fatal nosocomial infections in humans; multi-antibiotic resistance makes this organism a serious threat in hospital settings. Objective – To describe the historical, clinicopathological and treatment characteristics of Bcc-associated deep skin infections in dogs. Animals – Six dogs with skin infections in which skin bacterial cultures resulted in pure growth of Bcc. Methods – Retrospective study with review of medical records and skin biopsies. Results – All dogs were receiving oral ciclosporin at the time of skin infection development. All dogs were castrated males and four of six were West Highland white terriers. Cutaneous lesions consistent with deep pyoderma were confined mainly to the trunk. In all dogs skin cytology revealed a strong inflammatory response, with moderate to abundant numbers of intracellular (neutrophils and macrophages) and extracellular bacilli. In three dogs histopathology showed a multifocal, nodular to coalescing pyogranulomatous dermatitis associated with multifocal folliculitis and furunculosis. Tissue Giemsa and Gram stains identified numerous Gram-negative rods within macrophages. Antimicrobial susceptibility testing revealed multidrug-resistant Bcc strains with sensitivity to trimethoprim/sulfonamides in all dogs and to marbofloxacin, piperacillin and ceftazidime in three dogs. Successful treatment was achieved in all dogs using trimethoprim/sulfonamides or quinolones (marbofloxacin, ciprofloxacin) or doxycycline in conjunction with ciclosporin withdrawal. Conclusions and clinical importance – Clinicians should be aware of the rare potential for Bcc-associated deep skin infections in dogs receiving oral ciclosporin. Owners should be made conscious of the potential transmission risk to humans or other animals.
Introduction The Burkholderia cepacia complex (Bcc), formerly Pseudomonas cepacia, represents a group of phenotypically similar, but genetically distinct, motile, aerobic, glucosenonfermenting Gram-negative bacilli.1 These bacteria are widely distributed in the natural environment and can be isolated from water, soil, fruits and vegetables.1 Burkholderia organisms rarely cause infections in immunocompetent hosts, but Bcc has emerged as an important opportunistic pathogen in hospitalized (i.e. nosocomial infection) and immunocompromised patients.2
Accepted 23 February 2015 Sources of Funding: This study was self-funded. Conflict of Interest: No conflicts of interest have been declared. © 2015 ESVD and ACVD, Veterinary Dermatology
This report describes the historical, clinicopathological and treatment characteristics of Bcc deep skin infections in six dogs treated with ciclosporin orally.
Case reports Electronic medical records were searched at three institutions for skin bacterial culture results having yielded pure growth of Bcc organisms between the periods of 1999 (institution 1), 2005 (institution 2), 2008 (institution 3) and 2014; six dogs met this criterion and were included in this report. Signalment and history Signalment and historical data on the six dogs are summarized in Table 1. All dogs were castrated males and four of six were West Highland white terriers. All dogs had a previous history of a skin disease (four 1
Banovic et al.
Table 1. Signalment and historical features of six dogs with Burkholderia cepacia complex pyoderma Treatments for skin disease and duration before the diagnosis of B. cepacia complex pyoderma (days)
Age (years)
Sex
Weight (kg)
Prior skin disease
6.5
MC
39
Sebaceous adenitis
Dog
Breed
Case 1
Old English sheepdog
Case 2
West Highland white terrier
11
MC
9.7
Atopic dermatitis
Case 3
West Highland white terrier
3
MC
6.7
Atopic dermatitis
Case 4
West Highland white terrier
3.2
MC
10.3
Atopic dermatitis
Case 5
Dachshund
2.5
MC
7.7
Case 6
West Highland white terrier
1.8
MC
12
Sebaceous adenitis Atopic dermatitis
Ciclosporin 5.1 mg/kg once daily, ketoconazole 5.1 mg/kg once daily (90 days) Ciclosporin 5.1 mg/kg once daily (45 days) Ciclosporin 7.4 mg/kg every other day (320 days) Ciclosporin 4.8 mg/kg once daily 5 days/week, ketoconazole 4.8 mg/kg once daily 2 days/week (65 days) Ciclosporin 4.8 mg/kg once daily, vitamin A (8000 IU) once daily, x3 fatty acids once daily (345 days) Ciclosporin 5 mg/kg once daily, prednisone 0.4 mg/kg every other day (34 days)
Prior noncutaneous disease None
Diabetes mellitus Diabetes mellitus None
None
None
Abbreviation: MC, male castrated.
atopic dermatitis and two sebaceous adenitis) that was managed with ciclosporin (range 4.8–7.4 mg/kg, mean 5.3 mg/kg), in conjunction with ketoconazole in two dogs. Four of six dogs developed skin lesions within 3 months of starting ciclosporin, the other two after 8 months. The owners reported the acute dissemination from initial single lesions to multiple in a diffuse pattern. In dog 3, which suffered from diabetic ketoacidosis at presentation, skin lesions developed immediately after dorsal placement of a glucose-monitoring system device. An association with other predisposing factors could not be found for the other dogs apart from diabetes mellitus (dog 2) and immunomodulating therapy. An extracutaneous spread of Bcc bacteria was not reported for any dogs; blood cultures were not performed, however. Dermatological examination Lesions of Bcc infection seemed restricted to the skin. In all dogs, cutaneous lesions were confined to the trunk and upper limbs. These lesions consisted of multifocal irregular, erythematous to haemorrhagic alopecic papules, plaques and nodules, with extensive crusting, draining tracts and ulceration (Figure 1). In dog 3 (Figure 1c), lesions on the dorsum clustered into a severe diffuse linear cellulitis. Some lesions appeared as punched-out deep ulcers (Figure 1a,b). Lesions were mildly to severely painful on palpation in all patients. All dogs exhibited peripheral lymphadenopathy, while three dogs were hyperthermic and inappetent. Cytological findings Skin cytology in all dogs revealed a marked inflammatory response consisting of nondegenerative and degenerative neutrophils and macrophages, with moderate to abundant numbers of intracellular (neutrophils and macrophages) and extracellular rods. Few cocci in neutrophils were additionally seen in two dogs (dogs 2 and 5). 2
Bacterial culture and susceptibility testing Three different veterinary diagnostic laboratories identified Bcc organisms and determined antimicrobial susceptibility and interpretations (susceptible, intermediate and resistant) following Clinical and Laboratory Standards Institute guidelines. Pure cultures of Bcc bacteria were isolated from skin lesions in all dogs. The degree of bacterial growth was described as light (dog 5), moderate (dogs 1 and 2) or heavy (dogs 3, 4 and 6). Antibiotics to which isolates were reported resistant by the broth microdilution method included amikacin, amoxicillin/clavulanic acid, cefalexin, cefpodoxime, ceftiofur, cefovecin, chloramphenicol, gentamicin and tobramycin in all six dogs and tetracycline and enrofloxacin in five of the six dogs. Antibiotics to which isolates were reported to be sensitive included trimethoprim/sulfonamides in all dogs and marbofloxacin, piperacillin and ceftazidime in three of the six dogs (Table 2). Dermatopathology Microscopic examination of skin samples acquired via a punch biopsy from three dogs (dogs 1, 4 and 5) revealed similar changes: these consisted of multifocal, nodular to coalescing pyogranulomatous dermatitis attributed to multifocal folliculitis and furunculosis (Figure 2a,b). In all dogs, the inflammation extended to the panniculus. Varying degrees of epidermal hyperplasia, with several intrafollicular to subcorneal pustules (dog 1) and ulcerative dermatitis (all dogs) were noted. Tissue Giemsa and Gram stains identified numerous Gram-negative rods within macrophages and free in the dermis and panniculus (Figure 2b,c). Treatment approach and outcome Complete resolution of skin lesions in all dogs was obtained with appropriate therapy continued for up to 3 weeks beyond clinical resolution (Table 2). Dogs receiving trimethoprim/sulfonamides developed expected adverse effects, such as anaemia, clinical hypothyroidism © 2015 ESVD and ACVD, Veterinary Dermatology
Burkholderia cepacia pyoderma in dogs
a
b
c
d
Figure 1. (a) Multifocal deep erythematous to haemorrhagic ulcers with punched-out appearance after crust removal on the thorax of dog 5. (b and inset) Multifocal proliferative to ulcerated papules and crusted plaques in dog 1 with sebaceous adenitis. (c) Diffuse linear proliferative erythematous plaques with serosanguinous exudate on the mid-dorsum in dog 3. (d) Resolution of the same lesion from dog 3 (c) with scarring and alopecia. Table 2. Treatment approach and outcome in six dogs with B. cepacia pyoderma Systemic antibacterial therapy
Dog
Antimicrobial sensitivity
Immunomodulatory drugs after diagnosis
Before diagnosis (duration)
After diagnosis (duration until CR)
Case 1
Ceftazidime, piperacillin, TMS
Discontinued after 1 week
Cefalexin 25.6 mg/kg twice daily (2 weeks)
CR
Case 2
Ciprofloxacin, marbofloxacin, piperacillin, TMS Ciprofloxacin, marbofloxacin, piperacillin, TMS Ceftazidime, tetracycline, TMS
Continued without any changes Discontinued immediately Discontinued immediately
Case 5
Enrofloxacin, marbofloxacin, TMS
Discontinued ciclosporin after 6 weeks; prednisone 1.9 mg/kg once daily for 2 weeks, then tapered
Clindamycin 15.4 mg/kg twice daily (7 days) Enrofloxacin 10.1 mg/kg once daily (30 days) Enrofloxacin 4.8 mg/kg once daily, clindamycin 7.2 mg/kg twice daily (both 4 weeks) Cefpodoxime 6.4 mg/kg once daily (5 days)
TMS 36 mg/kg twice daily (2 weeks), rifampin 3.8 mg/kg twice daily (33 days), clindamycin 11.5 mg/kg twice daily (19 days) Ciprofloxacin 25.7 mg/kg once daily (8 weeks) Marbofloxacin 5.5 mg/kg once daily (12 weeks) Doxycyline 4.8 mg/kg once daily (6 weeks)
CR
Case 6
TMS
Discontinued immediately
Marbofloxacin 3.2 mg/kg once daily (4 weeks), then enrofloxacin 4.4 mg/kg once daily (2 weeks), then enrofloxacin 8.8 mg/kg once daily (12 weeks) and TMS 31.1 mg/kg twice daily (4 weeks) TMS 20 mg/kg twice daily (8 weeks)
Case 3 Case 4
Clindamycin 12.5 mg/kg once daily, enrofloxacin 6.2 mg/kg once daily (2 weeks)
Outcome
CR CR CR
CR
Abbreviations: CR, complete remission; TMS, trimethoprim/sulfonamide.
(dog 5) and keratoconjunctivitis sicca (dog 1). In dog 5, episodes of trembling, agitation and restlessness were noted after marbofloxacin administration. Five dogs © 2015 ESVD and ACVD, Veterinary Dermatology
received topical baths twice weekly with a chlorhexidine medicated shampoo. Topical mupirocin ointment (dog 1) and 1% silver sulfadiazine cream (dog 6) were applied 3
Banovic et al.
a
b
c
Figure 2. (a) Severe folliculitis and furunculosis with pyogranulomatous inflammation in dog 4. Haematoxylin and eosin; 95 magnification. (b) Higher magnification of (a; white inset). Numerous free rod-shaped bacteria (arrows) in the hair follicle wall. Giemsa; 960 magnification. (c) Higher magnification of (a; black inset). Numerous intracellular rod-shaped bacteria are seen in macrophages. Giemsa; 960 magnification.
twice daily until complete skin resolution. Immunomodulating drugs were eventually discontinued in all dogs except for dog 2. After 6 weeks, clinical improvement in dog 5 was mild, and subsequent blood monitoring revealed a ciclosporin trough level of 102 ng/mL. Ciclosporin was then discontinued, with moderate clinical improvement reported in the following 2 weeks. After complete resolution, ciclosporin was restarted only in dog 1 (5 mg/kg, once daily without ketoconazole); a recurrence of Bcc-associated skin lesions was not reported in any dogs over several years of follow-up. The long-term management of atopic dogs consisted of weekly topical antiseptic shampoo and glucocorticoid therapy, intermittent short courses of oral glucocorticoids and immunotherapy, while dog 5, with sebaceous adenitis, achieved moderate improvement with oral vitamin A and topical twice weekly baby oil soaks and antiseborrhoeic shampoo.
Discussion There are only rare reports of Bcc cutaneous infection in veterinary medicine; these include subclinical mastitis in a large flock of dairy sheep and cutaneous abscesses in an emaciated ewe.3,4 Previous descriptions of Bcc-associated skin infections in small animals were not identified. In this report, all dogs exhibited deep pyoderma with an acute evolution, which was associated with cellulitis in 4
some patients. Unlike acute Pseudomonas aeruginosaassociated pyoderma in dogs,5 the skin lesions of Bcc infection were widespread and, although painful, did not require sedation for diagnostic work-up. Interestingly, male castrated West Highland white terriers seemed over-represented, but a specific breed predisposition could not be evaluated because of the multicentre retrospective nature of this report and the lack of a reference population. Invasive Bcc infections, such as fatal necrotizing pneumonia and septicaemia, have been shown to occur in humans with the immunodeficiency associated with cystic fibrosis and chronic granulomatous disease.6,7 In humans, ciclosporin therapy, diabetes mellitus and Bcc bacteraemia are known to predispose to deep Bcc skin infections.8,9 While two of the dogs in this report had suffered from diabetes mellitus, all six dogs received oral ciclosporin at varying dosages and duration; two dogs also received concurrent ketoconazole for ciclosporin dosereduction purposes.10,11 High ciclosporin levels have been suspected to lead to the development of cutaneous nocardiosis in a dog.12 In this case series, a trough ciclosporin blood concentration was measured in only one dog, and it was lower than that needed for immunosuppression for organ transplantation in dogs (i.e. a range of 400–600 ng/mL).13 Measurement of ciclosporin trough concentrations in future cases of suspected ciclosporinassociated opportunistic infections may assist in clarifying © 2015 ESVD and ACVD, Veterinary Dermatology
Burkholderia cepacia pyoderma in dogs
the role of high ciclosporin levels for development of these rare events. Unlike other opportunistic pathogens, Bcc bacteria are not normally carried as commensal organisms on human or canine skin.14,15 As a result, the organisms are acquired either nosocomially or from the environment. While Bcc have useful commercial properties in agriculture as biocontrol agents and biopesticides, nosocomial outbreaks have been associated with contaminated disinfectants, hospital tap water, intravenous solutions, human transmission and medical devices.16–20 In companion animal veterinary practices, the demonstration of an environmental presence of Bcc has been limited to two reports revealing the contamination of surgical cold sterile solutions and of commercial ear-cleaner solutions.21,22 Although Bcc have been implicated in otitis media in mice, Bcc have not been reported as a causative agent of otitis in companion animals, to the authors’ knowledge.23 In this report, even though the owners implicated a causal association of Bcc pyoderma with a medical device placement in one dog, antiseptic solution or medical device contamination was not confirmed using bacterial cultures. Like P. aeruginosa, Bcc species have several antimicrobial protection mechanisms that, under antimicrobial pressure, could confer resistance to several classes of antibiotics, such as aminoglycosides, b-lactams, trimethoprim/sulfonamides, chloramphenicol and quinolones.24 In a retrospective antimicrobial susceptibility analysis of 50 Bcc isolated from ear, nasopharynx, uterus, urine and bronchoalveolar lavages of small animals, a susceptibility to trimethoprim/sulfonamides, imipenem and cefquinome was most common.25 In this report, Bcc strains were found to be sensitive to trimethoprim/sulfonamides (all dogs), followed by marbofloxacin, piperacillin and ceftazidime (three dogs). In humans with cystic fibrosis and chronic granulomatous disease, recommendations for pulmonary Bcc treatment include the use of intravenous meropenem plus one of the following: ceftazidime, chloramphenicol, trimethoprim/sulfonamides or aztreonam.26 In this report, successful treatment of Bcc skin infections was achieved using trimethoprim/sulfonamides, quinolones (marbofloxacin, ciprofloxacin) or doxycycline. In conclusion, this report represents, to the best of the authors’ knowledge, the first description of successfully treated Bcc-associated deep pyoderma in dogs. While all the dogs of this report were receiving ciclosporin immunomodulation, it is likely that Bcc pyodermas associated with other immunodeficient states also exist.
Acknowledgments We would like to thank Maarja Uri for providing us with clinical photographs.
2.
3.
4.
5.
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7.
8.
9.
10. 11.
12.
13.
14. 15.
16.
17.
18. 19.
20.
21.
22.
References 23. €bel UB. Stenotrophomonas maltophilia and 1. Maschmeyer G, Go Burkholderia cepacia. In: Mandell GA, Bennett JE, Dolin R, Gerald L, eds. Principles and Practice of Infectious Diseases. 6th
© 2015 ESVD and ACVD, Veterinary Dermatology
edition. Philadelphia, PA, USA: Churchill Livingstone, 2005; 2615–2622. Huang CH, Jang TN, Liu CY et al. Characteristics of patients with Burkholderia cepacia bacteremia. J Microbiol Immunol Infect 2001; 34: 215–219. Berriatua E, Ziluaga I, Miguel-Virto C et al. Outbreak of subclinical mastitis in a flock of dairy sheep associated with Burkholderia cepacia complex infection. J Clin Microbiol 2001; 39: 990–994. Al Dughaym AM. Isolation of Serratia, Arcanobacterium and Burkholderia species from visceral and cutaneous abscesses in four emaciated ewes. Vet Rec 2004; 155: 425–426. Hillier A, Alcorn JR, Cole LK et al. Pyoderma caused by Pseudomonas aeruginosa infection in dogs: 20 cases. Vet Dermatol 2006; 17: 432–439. Drevinek P, Mahenthiralingam E. Burkholderia cenocepacia in cystic fibrosis: epidemiology and molecular mechanisms of virulence. Clin Microbiol Infect 2010; 16: 821–830. Winkelstein JA, Marino MC, Johnston RB Jr et al. Chronic granulomatous disease: report on a national registry of 368 patients. Medicine 2000; 79: 155–169. €zeri B et al. Soft tissue infection caused by Yıldız B, Duyu M, So Burkholderia cepacia in a child with polyarteritis nodosa. Turk J Pediatr 2012; 54: 664–666. Fadini GP, Tiengo A, Avogaro A. First isolation of Burkholderia cepacia from a deep neck abscess in a diabetic patient successfully treated with hyperbaric oxygen. J Clin Microbiol 2005; 43: 529. Dahlinger J, Gregory C, Bea J. Effect of ketoconazole on cyclosporine dose in healthy dogs. Vet Surg 1998; 27: 64–68. Gray LL, Hillier A, Cole LK et al. The effect of ketoconazole on whole blood and skin ciclosporin concentrations in dogs. Vet Dermatol 2013; 24: 118–125. Siak MK, Burrows AK. Cutaneous nocardiosis in two dogs receiving ciclosporin therapy for the management of canine atopic dermatitis. Vet Dermatol 2013; 24: 453–456. Mathews KA, Holmberg DL, Miller CW. Kidney transplantation in dogs with naturally occurring end-stage renal disease. J Am Anim Hosp Assoc 2000; 36: 294–301. Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol 2011; 9: 244–253. Rodrigues Hoffmann A, Patterson AP, Diesel A et al. The skin microbiome in healthy and allergic dogs. PLoS ONE 2014; 9: e83197. Holmes A, Govan J, Goldstein R. Agricultural use of Burkholderia (Pseudomonas) cepacia: a threat to human health? Emerg Infect Dis 1998; 4: 221–227. Hutchinson GR, Parker S, Pryor JA et al. Home-use nebulizers: a potential primary source of Burkholderia cepacia and other colistin-resistant, Gram-negative bacteria in patients with cystic fibrosis. J Clin Microbiol 1996; 34: 584–587. Oie S, Kamiya A. Microbial contamination of antiseptics and disinfectants. Am J Infect Control 1996; 24: 389–395. Fung SK, Dick H, Devlin H et al. Transmissibility and infection control implications of Burkholderia cepacia in cystic fibrosis. Can Infect Dis J 1998; 9: 177–182. Nasser RM, Rahi AC, Haddad MF et al. Outbreak of Burkholderia cepacia bacteremia traced to contaminated hospital water used for dilution of an alcohol skin antiseptic. Infect Control Hosp Epidemiol 2004; 25: 231–239. Murphy CP, Weese JS, Reid-Smith RJ et al. The prevalence of bacterial contamination of surgical cold sterile solutions from community companion animal veterinary practices in southern Ontario. Can Vet J 2010; 51: 634–636. Bartlett SJ, Rosenkrantz WS, Sanchez S. Bacterial contamination of commercial ear cleaners following routine home use. Vet Dermatol 2011; 22: 546–553. Hobson R, Gould I, Govan J. Burkholderia (Pseudomonas) cepacia as a cause of brain abscesses secondary to chronic suppurative otitis media. Eur J Clin Microbiol Infect Dis 1995; 14: 908– 911.
5
Banovic et al.
24. Hancock RE. Resistance mechanisms in Pseudomonas aeruginosa and other nonfermentative gram-negative bacteria. Clin Infect Dis 1998; 27: 93–99. 25. Attili AR, Tambella AM, Preziuso S et al. Burkholderia cepacia complex in clinically-infected animals: retrospective analysis, antibiotic resistance, and potential hazard for public health. In Proceedings of the 23rd European Society of Clinical Microbiol-
ogy and Infectious Diseases, 2013; 1450 (Abstract). Available at: https://www.escmid.org/escmid_library/online_lecture_library/ material/?mid=7107. Accessed Mar 1, 2015. 26. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–951.
sume Re ries du complexe Burkholderia cepacia (Bcc) sont des bacilles ram ne gatives ubiquiContexte – Les bacte es a des infectons nosocomiales mortelles chez l’homme; des re sistances multiples aux antitaires associe rieuse dans le milieu hospitalier. biotiques font de ces organismes une menace se crire les caracte ristiques anamnestiques, clinicopathologiques et the rapeutiques des infecObjectif – De tions profondes a Bcc chez le chien. sentant une infection cutane e avec une culture bacte riologique de Bcc pure. Sujets – Six chiens pre thodes – Etude re trospective avec revue des donne es me dicales et des biopsies cutane es. Me sultats – Tous les chiens recevaient de la ciclosporine orale au moment du de veloppement de l’infection Re e. Tous les chiens e taient des m^ales castre s et quatre sur six e taient des West Highland white terricutane sions cutane es consistaient en une pyodermite profonde principalement localise e au tronc. Pour ers. Les le e re ve lait une intense re ponse inflammatoire avec un nombre mode re tous les chiens une cytologie cutane a important de bacilles intracellulaires (neutrophiles et macrophages) et extracellulaires. Pour trois chiens, ve lait une dermatite pyogranulomateuse multifocale, nodulaire e l’histopathologie re a coalescente associe a une folliculite et furonculose multifocale. Les colorations Giemsa et Gram re ve laient de nombreux b^ atongatifs au sein de macrophages. L’antibiogramme re ve laient des souches de Bcc multire sisnets Gram ne toprimes/sulfamide s chez tous les chiens et pour trois chiens tantes sensible a aux trime a la te re alise pour tous les chiens avec marbofloxacine, piperacilline et ceftazidime. Un traitement efficace a e ^t trimethoprime/sulfonamides ou quinolones (marbofloxacine, ciprofloxacine) ou doxycycline associe a l’arre de la ciclosporine. Conclusions et importance clinique – Les cliniciens doivent suspecter le rare potentiel des infections es profondes lie es a Bcc chez les chiens recevant de la ciclosporine orale. Les proprie taires doivent cutane ^tre avertis du risque de transmission a l’homme et aux autres animaux. e Resumen n – las bacterias del complejo Burkholdera cepacia (Bcc) son bacilos Gram negativos ubicuos Introduccio ticos mu ltiples hace asociados con infecciones nosocomiales fatales en humanos; la resistencia a antibio de este organismo un riesgo muy serio en hospitales. ricas, clınico-patolo gicas y el tratamiento de infecciones profunObjetivo – describir las caracterısticas histo das de la piel de perros asociados con Bcc. Animales – seis perros con infecciones de la piel con cultivo puro de Bcc. todos – estudio retrospectivo con revisio n de los historiales clınicos y biopsias de piel Me Resultados – todos los perros estaban recibiendo ciclosporina oral en el momento del desarrollo de la inn de la piel. Todos los perros eran machos castrados y cuatro de ellos eran de la raza West Highland feccio White Terrier. Las lesiones cutaneas consistieron en pioderma profunda restringida fundamentalmente a la una respuesta inflamatoria intensa con zona del tronco. En todos los perros la citologıa de la piel revelo filos y macro fagos) y extracelulares. meros moderados a abundantes de bacilos intracelulares (en neutro nu una dermatitis multifocal, nodular a confluente piogranulomaEn tres de los perros la histopatologıa mostro tosa asociada con foliculitis multifocal y furunculosis. Las tinciones de Giemsa y Gram para tejidos identififagos. Las pruebas de susceptibilidad caron numerosos bacilos Gram negativos dentro de macro ltiple a los f antimicrobiana revelaron cepas de Bcc con resistencia mu armacos y sensibilidad a trimetoprima/sulfonamida en todos los perros y a marbofloxacina, piperacilina y ceftazidima en tres perros. Se obtuvo un tratamiento eficaz en todos los perros utilizando trimetoprima/sulfonamida o quinolonas (marbofloxacina, ciprofloxacina) o doxiciclina conjuntamente con la retirada del tratamiento de ciclosporina Conclusiones e importancia clınica – los clınicos deben conocer el raro potencial de desarrollar infecciones profundas de la piel producidas por Bcc en perros recibiendo ciclosporina oral. Los propietarios deben n a humanos y a otros animales. ser conscientes del potencial de transmisio Zusammenfassung Hintergrund – Bakterien des Burkholderia cepacia Komplexes (Bcc) sind ubiquit€ are Gram-negative Bazil€dlichen nosokomialen Infektionen des Menschen auftreten; die multiple Resistenz gegen Anlen, die bei to tibiotika macht diesen Organismus zu einer gef€ ahrlichen Bedrohung in Krankenh€ ausern. Ziel – Eine Beschreibung der Anamnese, der klinischen Pathologie und der Behandlungscharakteristika die mit Bcc auftretenden tiefen Hautinfektionen bei Hunden. 6
© 2015 ESVD and ACVD, Veterinary Dermatology
Burkholderia cepacia pyoderma in dogs
Tiere – Sechs Hunde mit Hautinfektionen, bei denen die Bakterienkulturen ein reines Wachstum von Bcc ergaben. Methoden – Es handelt sich um eine retrospektive Studie mit einer Review der medizinischen Patientendaten und der Hautbiopsien. Ergebnisse – Alle Hunde erhielten zum Zeitpunkt der Entstehung der Hautinfektion Ciclosporin per os. Alle €den und vier waren West Highland White Terrier. Die Hautver€ Hunde waren kastrierte Ru anderungen entsprachen einer tiefen Pyodermie und waren haupts€ achlich auf den Rumpf beschr€ ankt. Bei allen Hunden ze€ndliche Reaktion, mit moderaten bis zahlreichen intrazellul€ igte die Zytologie eine starke entzu aren (Neutrophile und Makrophagen) und extrazellul€ aren Bazillen. Bei drei Hunden zeigte die Histopathologie €se Dermatitis, die gemeinsam mit einer multieine multifokale, knotige bis koaleszierende pyogranulomato fokalen Follikulitis und Furunkulose auftrat. Giemsa und Gramf€ arbungen der Gewebe ergaben zahlreiche Gram-negative St€abchen in den Makrophagen. Eine Bakterienkultur mit Antibiogramm ergab einen multiresistenten Bcc Stamm mit einer Sensibilit€ at auf Trimethoprim/Sulfonamide bei allen Hunden und auf Marbofloxacin, Piperacillin und Ceftazidime bei drei Hunden. Eine erfolgreiche Behandlung wurde bei allen Hunden mit Trimethoprim/Sulfonamide oder Quinolonen (Marbofloxacin, Ciprofloxacin) oder Doxycyclin in Verbindung mit einem Absetzen von Ciclosporin erzielt. Schlussfolgerungen und klinische Bedeutung – KlinikerInnen sollten sich bewusst sein, dass tiefe Haut€nnen. Die BesitzerIninfektionen durch Bcc bei Hunden, denen Ciclosporin verabreicht wird, auftreten ko € €gliche Ubertragungsrisiken €ber mo nen sollten u auf Menschen oder andere Tiere aufmerksam gemacht werden. 摘要 背景 – 洋葱伯克霍尔德菌复合物(Bcc)细菌无处不在,是引起人严重感染的革兰氏阴性杆菌;多重抗生素耐药 性使得其极难治疗。 目的 – 描述犬Bcc导致皮肤感染的病史、临床发病机理和治疗特点。 动物 – 六只皮肤感染的犬,皮肤细菌培养结果为纯Bcc增殖。 方法 – 回顾性研究诊疗纪录和皮肤活检结果。 结果 – 所有犬在皮肤感染时期均口服环孢素。所有犬为去势公犬,六只中的四只为西高地白㹴。皮肤病变属 于深度脓皮病,主要集中在躯干部。所有犬的细胞学显示严重的炎症反应,伴有中度的细胞内(中性粒细胞和 巨噬细胞)及细胞外杆菌。三只犬的组织病理学显示为多病灶、结节性聚集的脓性肉芽肿性皮炎,多病灶性毛 囊炎及疖病。组织姬姆萨和革兰氏染色显示巨噬细胞内有许多革兰氏阴性杆菌。药敏试验显示Bcc菌株多重 耐药性,所有犬甲氧苄氨嘧啶/磺胺类敏感,三只犬马坡沙星、派拉西林和头孢他啶敏感。所有犬使用甲氧苄 氨嘧啶/磺胺类,或喹诺酮类(马波沙星、环丙沙星),或配合多西环素,同时停用环孢素治疗成功。 总结与临床意义 – 临床医生应了解,尽管罕见,使用环孢素的犬有Bcc导致深度皮肤感染的可能。主人应意识 到有传染给人类或其他动物的潜在风险。 要約 背景 – Burkholderia cepacia複合体(Bcc)の細菌はいたるところに存在する、ヒトで致命的な院内感染に関連する グラム陰性桿菌であり、複数の抗菌剤耐性によりこの微生物が病院内の環境において深刻な脅威となっている。 目的 – イヌにおけるBcc関連性深在性皮膚感染症の歴史、臨床病理、治療の特徴を解説すること。 供与動物 – Bccの純粋増殖が皮膚細菌培養検査の結果として得られた、皮膚感染のある6頭のイヌ。 方法 – 診療記録と皮膚生検の再検討による回顧的研究 結果 – すべてのイヌが皮膚感染発生時に経口シクロスポリンを投与されていた。すべてのイヌは去勢雄で、6頭中4頭 がウエストハイランドホワイトテリアであった。皮膚病変は深在性膿皮症と一致し、主に体幹部に限定して認められた。す べてのイヌの皮膚細胞診において、中程度から豊富な数の細胞内(好中球およびマクロファージ)および細胞外桿菌を 伴う、強い炎症性反応が明らかになった。3頭のイヌでは病理組織は多病巣性の毛包炎やフルンケローシスを伴う、 多病巣性で結節性から癒合性の化膿性肉芽腫性皮膚炎を示していた。組織のギムザ染色およびグラム染色は多数 のグラム陰性桿菌をマクロファージ内に特定した。抗菌剤感受性試験はトリメトプリム/スルフォンアミドに感受性の多剤 耐性Bcc株をすべてのイヌで、マルボフロキサシン、ピペラシン、セフタジジムに感受性の多剤耐性Bcc株を3頭のイヌ で明らかにした。すべてのイヌにおいて、トリメトプリム/スルフォンアミドあるいはキノロン(マルボフロキサシン、シプロフロキサ シン)、あるいはドキシサイクリンの使用とシクロスポリンの休薬とともに治療が成功した。 結論および臨床的な重要性 – 臨床家は経口シクロスポリン投与をしているイヌにおいてBcc関連性深在性皮膚感染症 の稀な可能性に注意すべきである。飼い主はヒトや他の動物に対する潜在的な伝染のリスクを意識するべきである。
© 2015 ESVD and ACVD, Veterinary Dermatology
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