Treatment of nontuberculous mycobacterial lymphadenitis with clarithromycin plus rifabutin

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Treatment of nontuberculous mycobacterial lymphadenitis with clarithromycin plus rifabutin Christoph Berger, MD, G a b y E, Pfyffer, PhD, a n d D a v i d N a d a l , MD From the Infectious DiseasesUnit, UniversityChildren's Hospital, Zurich, and the SwissNational Center for Mycobacteria, Department of Medical Microbiology, Universityof Zurich, Zurich, Switzerland Treatment with clarithromycin plus rifabutin in children with nontuberculous mycobacterial lymphadenitis was associated with resolution of chronic sinus formation and discharge after incomplete excision in five of five cases, and involution of the enlarged lymph nodes in two of three cases treated without surgery. (J PE" DIATR 1996; 128:383-6) Cervicofacial lymphadenitis is the most common manifestation of infection with nontuberculous mycobacteria in childhood. Mycobacterium avium-intracellulare complex accounts for 70% to 90% of the cases. 1 The treatment of choice is total surgical excision of the affected lymph nodes.2 However, complete excision risks injuring branches of the facial nerve, and incomplete excision or mere incision is often complicated by chronic sinus formation and discharge., Such cases would benefit from effective antimicrobial therapy. We report the treatment with" clarithromycin plus rifabutin of eight children with NTM lymphadenitis in whom complete excision of the lymph node was not possible or was refused.

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dia for mycobacteria included a L6wenstein-Jensen slant, Middelbrook Cohn 7H10/selective 7H1 l agar, and the radiometric BACTEC 12B medium (Becton Dickinson, Diagnostic Instrument Systems, Sparks, Md.). Susceptibility of NTM to clarithromycin and rifabutin was determined by the proportion method. 3 Antimicrobial treatment. Orally administered clarithromycin (7.5 mg/kg twice daily as an oral suspension; Klaciped, Abbott) plus rifabntin (5 mg/kg once daily) were given for 6 months. For each patient the adequate amount of rifabutin was packed into capsules by our pharmacist. Fol-

I

MAC Mycobacteriumavium-intracellulare complex NTM Nontuberculous mycobacteria

I

METHODS Patients. We prospectively studied (1) children with culture-proven NTM lymphadenitis, with sinus formation after incomplete surgical excision, and (2) children with suspected NTM lymphadenitis 1'~- for whom parents or surgeons refused surgery for fear of injuring the facial nerve. Lymphadenitis caused by NTM was suspected in children with unilateral, cervical or facial, indolent lymphadenopathy with a blue-black overlying skin.~ All patients seen at our outpatient clinic who met this definition were included in this study. Microbiology and susceptibility testing. Excised lymph node tissue was examined histologically and for bacteria, fungi, and mycobactefia by standard methods. Culture meSubmitted for publication Aug. 11, 1995; accepted Oct. 27, 1995. Reprint requests: David Nadal, MD, University Children's Hospital, Infectious Diseases Unit, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/26/70273

low-up visits with blood cell count and liver function tests were scheduled at 6-week intervals. Adherence to treatment was assessed by measuring the volume of suspension and the number of capsules used. RESULTS

Patient characteristics. Between August 1993 and March 1995 we studied eight children (Table). Before referral, treatment with [3-1actam antibiotics for six patients had shown no clinical benefit, incomplete surgical excision or fine needle biopsy for five patients had been complicated by chronic sinus formation and discharge, and surgery had been refused for three patients (Table). The affected lymph nodes in the latter three patients were indolent, sized 1 x 2 cm to 3 x 5 cm in diameter, and had a thin, black-blue overlying skin. Cultures of four of five lymph node specimens had grown MAC (Table). The results of our standard tuberculin skin test (2 IU RT23, which functionally correspond to 5 U PPD standard) were negative (<10 mm infiltration) in all

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The Journal of Pediatrics March 1996

Table. Characteristics of eight children with NTM lymphadenitis treated with clarithromycin plus rifabutin for 6 months History

Treatment with clarithromycin plus rifabutin

Lymphadenitis Patient No.

Gender, Prior age Duration antibiotic Surgical (mo) Localization (mo) treatment treatment

1

M, 32

Angular

2

OX/AMC Incomplete excision

2

F, 15

Submandibular

3

AMC

3

M, 28

Preauricular

3

AMC

4

M, 16

Submandibular

3

AMC

5

M, 23

Preauricular

1

None

6

M, 25

Submandibular

4

AMX

7

F, 34

Angular

5

None

8

F, 22

Angular

2

AMC

Histology

Culture

Granulomatous MAC inflammation

Refused ND ND by surgeon Incomplete Granulomatous MAC excision inflammation

Postoperative course*

Adverse effects

Outcome

Discharge Brownish film Cured persisting for on teeth 5 wk None Cured

Extensive Brownish film Cured swelling for 1 on teeth wk Refused Granulomatous MAC? Uncomplicatedj None Increasing by parents inflammation? fluctuation? Refused ND ND Brownish film Cured by surgeon on teeth; "['liver enzymes; Incomplete Granulomatous No Discharge None Cured excision inflammation growth persisting for 5 wk Incomplete Granulomatous MAC Discharge None Cured excision inflammation persisting for 11 wk Fine needle Granulomatous MAC Perforation 2 None Cured biopsy inflammation wk after puncture; discharge persisting for 5 wk

AMC, Amoxicillin-clavulanate;AMX, amoxicillin;OX, oxacillin;ND, not done; MAC, Mycobacteriumavium-intraceIlularecomplex. *Until treatmentwith clariflaromycinand rifabufinwas started. ~-Excisionafter 2 months because of increasingfluctuation. :~Alanineaminotransferase,73 U/L; aspartate aminotransferase,105 U/L.

cases. NTM skin test antigens were not available. Catscratch disease was ruled out by history and by serologic studies for Bartonella henselae. 4 Clinical response to study regimen. Oral treatment with clarithromycin plus rifabutin in all five patients with chronic sinus formation resulted in resolution of discharge within 2 months and subsequent scarring of the lesions. In patients without previous surgery, treatment was followed by involution of affected lymph nodes and normalization of the overlying skin layers within 2 months in two cases (patients 2 and 5; Table), but by fluctuation of the lymph node within 2 months in patient 4. Surgical excision was done in patient 4 after parental consent. Cultures grew MAC. The postoperative course was unremarkable. Adverse effects of the study regimen were brownish film on the teeth in three patients (Figure), which resolved 1

month after completion of treatment, and transient elevation of liver enzymes (alanine aminotransferase, 73 U/L; asparrate aminotransferase, 105 U/L) in one patient. I n vitro susceptibility of M A C . Four MAC isolates (from patients 1, 3, 4, and 6) were available for susceptibility testing. All isolates were resistant to clarithromycin at concentrations 6.0 mg/L or less. Resistance to fifabutin was detected in the isolate from patient 6, but only at the lower concentration (1.0 mg/L) tested. DISCUSSION Complete surgical excision of affected tissue is the treatment of choice of NTM lymphadenitis.2 Moreover, it enables establishing the clinically suspected cause by histologic examination and cultures; skin tests using NTM antigens may not be available. However, complete surgical excision of a

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Ngure. Brownish discoloration of the teeth in a 30-month-old boy (patient 3) treated with clarithromycin plus rifabutin.

cervicofacial lymph node may bear the risk of injuring branches of the facial nerve or be unattainable because of extension and the often crumbling nature of affected tissue. After incomplete excision or biopsy, chronic sinus formation may occur and may result in substantial cosmetic problems.I, 2 Primary antituberculous drugs have shown little effect on NTM.I' 2 Reports on the clinical efficacy of clarithromycin and rifabutin in patients with the acquired immunodeficiency syndrome and MAC infections5, 6 encouraged us to use the drugs in children with NTM lymphadenitis. Our study was not controlled, and the apparent efficacy of the antimicrobial agents could simply reflect the spontaneous course. However, it seems unlikely that the resolution of discharge and chronic sinus formation in all five patients after the start of the study regimen was coincidental. With respect to the three patients primarily treated with the study regimen, the etiologic diagnosis of NTM lymphadenitis was established only in the patient in whom fluctuation of the subsequently excised lymph node developed. Thus the involution of the enlarged lymph nodes in the two other patients could have been due to the efficacy of the study regimen against other pathogens, including staphylococci and streptococci. Involvement of such pathogens seems unlikely, however, because the lymphadenitis had persisted without treatment for at least 1 month and the cfihical findings and age of the patients were consistent with NTM lymphadenitis. 1 The progression of NTM lymphadenitis to a fluctuating process in one patient despite the study regimen may indicate that the time of starting such treatment may be decisive. Alternatively, suscep-

tibility of incriminated swains to antimicrobial agents may differ. Performing in vitro susceptibility testing on initial MAC isolates is still considered inappropriate and unnecessary in most clinical situations because the in vitro results lack both verified criteria and a correlation with therapeutic efficacy.3 The latter point is nicely illustrated by the results of our study, showing in vitro resistance (at -<6.0 rag/L) to clarithromycin and partial resistance to rifabutin. Our study regimen used recommended doses 5 and lasted 6 months in analogy to isoniazid preventive therapy for tuberculosis. The small number of patients and the uncontrolled study design cannot answer questions related to optimal dose and duration of treatment. Our observation that signs and symptoms resolved within 2 months in all but one patient, as well as other recent case reports, 7, 8 indicate that treatment for less than 6 months might be sufficient. In summary, treatment with clarithromycin plus rifabutin was associated with resolution of discharge and chronic sinus formation in children with NTM lymphadenitis, and may be of benefit in primary treatment of NTM lymphadenitis. REFERENCES

l. Wolinsky E. Mycobacterial lymphadenitis in children: a prospective study of 105 nontuberculous cases with long-term follow-up. Clin Infect Dis 1995;20:954.-63. 2. Schaad UB, Votteler TP, McCracken GH, Nelson JD. Management of atypical mycobacterial lymphadenitis in childhood: a review based on 380 cases. J PEDIaTR 1979;95:356-60. 3. Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH,

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eds. Manual of clinical microbiology. 6th ed. Washington, DC: ASM Press, t995. 4. Nadal D, Zbinden R. Serology to BartoneUa (Rochalimaea) henselae may replace traditional diagnostic criteria for catscratch disease. Eur J Pediatr 1995;154:906-8. 5. Masur H, Public Health Task Force on Prophylaxis and Therapy for Mycobacterium avium complex. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. N Engl J Med 1993;329:898-904.

The Journal of Pediatrics March 1996

6. Sullam PM, Gordin FM, Wynne BA, Rifabutin Treatment Group. Efficacy of rifabutin in the treatment of disseminated infection due to Mycobacterium avium complex. Clin Infect Dis 1994;19:84-6. 7. Clark JE, Magee JG, Cant AJ. Nontuberculous mycobacterial lymphadenopathy. Arch Dis Child 1995;72:165-6. 8. Tessier M-H, Amoric J-C, M6chinaud F, Dubesset D, Litoux P, Stalder J-P. Clarithromycin for atypical mycobacterial lymphadenitis in non-immunocompromised children [Letter], Lancet 1994;344:1778.

Extracorporeal membrane oxygenation as a bridge to definitive tracheal surgery in children Allan P. Goldman, MBChB, Duncan J. Macrae, MBChB, Robert C. Tasker, MBChB, Karl E. Edberg, MD, G6sta Mellgren, MD, Claus Herberhold, MD, Jeffrey P. Jacobs, MD, Ralph E. Delius, MD, and Martin J, Elliott, MD From The Cardiothoracic Unit, Great Ormond Street Hospital for Children, London, United Kingdom, Children's Hospital, G6teborg University, G6teborg, Sweden, and ENT Department, University of Bonn, Bonn, Germany

Extracorporeal membrane oxygenation was used as a bridge for three infants with complicated long segment congenital tracheal stenosis to tracheal homografl transplantation with cadaveric tracheal homografl and for one child, with an extensive traumatic tracheal laceration caused by aspiration of a sharp foreign body, to definitive tracheal repair. In all four cases mechanical ventilation was impossible and death almost certain without extracorporeal membrane oxygenation. (J PEDIATR1996; 128:386-8)

Extracorporeal membrane oxygenation has been widely used for cardiorespiratory support in neonatal diseases] and in infants and children with intractable cardiac 2 and respiratory failure, 3,4 as well as a bridge to heart and lung transplantation. 5 W e present four cases demonstrating the potential use of E C M O to provide acute oxygenation and carbon dioxide removal when mechanical ventilation is impossible because of major airway disease and disruption. CASE REPORTS Patient 1. A piece of aspirated porcelain foreign body became

embedded in the right main-stem bronchus of a previously healthy 13-month-old toddler during a failed attempt to remove the obstruction at another institution. The resulting massive extrusion of air made mechanical ventilation impossible, and the patient therefore received ECMO therapy as the only effective means of ventilatory support. An additional bronchoscopy showed a large porcelain chip with razor-sharp edges, which was removed from the

right main bronchus intermedins. The ECMO therapy was continued after bronchoscopy in an attempt to facilitate airway heating without the presence of an endotracheal tube; however, on day 4 of ECMO therapy the patient had extensive pulmonary hemorrhaging that required interventional management. Exploration revealed that the posterior tracheal tear was much more extensive than anticipated, extending from the cricoid to the middle of the ECMO LSCTS THT

Extracorporeal membrane oxygenation Long-segment congenital tracheal stenosis Tracheal homograft transplantation

right lowerlobe bronchus. The ECMO support was continued after tracheobronchial repair because the lungs still could not be adequately ventilated as a result of the preoperative pulmonary hemorrhage. High-frequency oscillatory ventilation was started to maximize alveolar recruitment. After 17 days ECMO therapy was discontinued and the endotracheal tube was removed 7 weeks later. The patient is now well at home 1 year after repair