The Clinical Management and Outcome of Nail Salon Acquired Mycobacterium fortuitum Skin Infection

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1 MAJOR ARTICLE The Clinical Management and Outcome of Nail Salon Acquired Mycobacterium fortuitum Skin Infection Kevin L. Winthrop, 1,2 Kim Albridge, a David South, a Peggy Albrecht, 4 Marcy Abrams, 3 Michael C. Samuel, 2 Wendy Leonard, 3 Joanna Wagner, 2 and Duc J. Vugia 2 1 Epidemic Intelligence Service, Epidemiology Program Office, Centers for Disease Control and Prevention and 2 Division of Communicable Disease Control, California Department of Health Services, Berkeley, and 3 Santa Cruz County Health Agency and 4 Santa Cruz Medical Clinic, Santa Cruz, California Nontuberculous mycobacterial infections are becoming more common. Recently, Mycobacterium fortuitum and other rapidly growing mycobacteria have been found to cause severe skin and soft-tissue infections in association with nail salon whirlpool footbaths. We recently investigated a large outbreak of M. fortuitum furunculosis among women who received pedicures at a single nail salon. To better define the clinical course of such infections, we collected clinical details from physicians who were treating outbreak patients. We constructed multivariable linear models to evaluate the effect of antibiotic treatment on disease duration. Sixty-one patients were included in the investigation. The mean disease duration was 170 days (range, days). Forty-eight persons received antibiotic therapy for a median period of 4 months (range, 1 6 months), and 13 persons were untreated. Isolates were most susceptible to ciprofloxacin and minocycline. Early administration of therapy was associated with shorter duration of disease only in persons with multiple boils ( P!.01). One untreated, healthy patient had lymphatic disease dissemination. Mycobacterium fortuitum is one of several rapidly growing mycobacteria that are ubiquitous in soil and water habitats [1 5]. These mycobacteria are known to cause cutaneous infection, typically in association with trauma or clinical procedures [6]. In 2002, however, Winthrop et al. [7] documented a large outbreak of community-acquired infection with rapidly growing mycobacteria. In this outbreak, 1115 patrons from a single Received 19 June 2003; accepted 18 August 2003; electronically published 8 December Presented in part: 40th Annual Meeting of the Infectious Diseases Society of America, Chicago, IL, 25 October 2002 (abstract 686). a Private practice, Watsonville, California. Reprints or correspondence: Dr. Kevin L. Winthrop, Div. of Tuberculosis Elimination/Field Services, Centers for Disease Control and Prevention at the California Dept. of Health Services, Rm. 608, 2151 Berkeley Way, Berkeley, CA (kow3@cdc.gov). Clinical Infectious Diseases 2004; 38:38 44 This article is in the public domain, and no copyright is claimed /2004/ nail salon contracted severe, lower-extremity M. fortuitum furunculosis from contaminated whirlpool footbaths used in the salon. Since this time, additional outbreaks and similar sporadic cases of disease have been reported [7 9], and it has become clear that whirlpool footbath associated mycobacterial infections are more widespread than was previously appreciated. Because such infections have only recently been recognized, their natural history and optimal clinical management have not yet been elucidated. To document the clinical and diagnostic features of these infections, we observed the clinical course of a subset of persons affected by the outbreak of M. fortuitum furunculosis reported by Winthrop et al. [7]. PATIENTS AND METHODS In this observational study, we followed a subset of case patients previously identified by Winthrop et al. [7] during an initial outbreak investigation conducted 38 CID 2004:38 (1 January) Winthrop et al.

2 in To enroll patients in the study, we identified clinicians who were treating at least 1 culture-confirmed case patient from the outbreak and asked them to enroll all of their outbreak case patients ( n p 62) into our study. Outbreak case patients were defined as persons who, after having receiving a pedicure at the outbreak salon during the period of April through October 2000, developed a persistent soft-tissue infection below the knee that lasted for 12 weeks and had 1 of the following features: negative results of a routine bacterial culture, no response to routine antibiotic therapy, or clinical suspicion of mycobacterial disease by the treating physician [7]. We asked physicians to complete a standardized questionnaire that gathered clinical details for each case patient. Details included medical history, treatment regimen, duration of clinically evident infection, and disease outcome. We also recorded results of culture and antibiotic susceptibility tests, as well as dermatopathological findings from examinations of skin punch biopsy tissue specimens. Disease duration was defined as the interval between the day of disease onset (reported by patients during the initial outbreak investigation) and the day of clinical resolution (reported by treating physicians). After disease resolution, physicians asked patients to immediately report any subsequent reactivation of disease. No attempt was made to modify or influence the duration or choice of treatment among physicians. Patient follow-up occurred at intervals determined by the treating physician. Patients who received 1 antibiotic (monotherapy) or 2 antibiotics concurrently (dual-agent therapy) directed against mycobacteria for 2 weeks were considered to be treated. Patients who received no antibiotic treatment, treatment with antibiotics typically not known to have in vitro activity against mycobacteria, or treatment with antibiotics with activity against mycobacteria for!2 weeks were considered to be untreated. We evaluated the independent effect of antibiotic treatment using a variable that adjusted for the elapsed time between disease onset and the initiation of treatment. With regard to this delay in therapy initiation, persons treated with antibiotics naturally clustered into 3 categories of roughly equal numbers on the basis of the following natural breakpoints in the data: those who began treatment 1 40 days, days, or 71 days after infection onset. All case patients were recommended to undergo skin punch biopsy for mycobacterial culture. Cultures of biopsy tissue specimens were either positive or negative for mycobacteria or were not performed. We attempted to control for differences in disease duration in our data that could arise because of varying levels of experience among physicians in treating these infections. To do so, we created a physician variable and categorized treating physicians as experienced or other on the basis of the number of patients they treated. Three dermatologists (i.e., experienced physicians) evaluated 30 (50%) of 61 case patients, whereas the remaining 31 case patients were evaluated by a total of 18 other physicians, most of whom were primary care physicians or infectious disease specialists. The number of boils was recorded at the time of the patient s first presentation to the treating physician. In our analysis, we explored the relationship between the number of boils and disease duration in a univariate fashion, retaining boils as a continuous variable, and then grouped the number of boils into 4 levels (1, 2 3, 3 4, and 5 boils). The only statistically important relationship between these 2 variables occurred between 1 and 2 boils. Therefore, this dichotomized variable construct (i.e., 1 and 2) was retained for further analysis in our model. All data were entered into EpiInfo 2000, version 1.1 (Centers for Disease Control and Prevention). Univariate and stratified analyses were conducted to identify relationships between disease duration and variables that could potentially influence disease duration. Comparison of means was done with analysis of variance, and comparison of continuous variables was performed with univariate linear regression. P values for univariate analysis were calculated using Student s t test. Multivariable linear models were then constructed using the Proc GenMod procedure in SAS statistical software (SAS Institute), to evaluate the independent effects of various explanatory factors on the outcome of disease duration. P values for multivariate analysis were calculated using the Wald test. RESULTS Follow-up information was available for 61 of 62 patients; 60 (98%) were female. Patient age ranged from 13 to 53 years. No persons were immunocompromised; 3 were pregnant at the time of infection. Patients had a median number of 2 boils each (range, 1 20 boils). All lesions were present below the knee in a distribution that corresponded to the area of leg exposed to water in the whirlpool footbaths used during the pedicure procedure. The clinical appearance and natural history of the lesions in this outbreak were strikingly uniform (figures 1 4). Lesions typically first presented as small papules with a spider-bite appearance. Papules underwent characteristic progression to large fluctuant boils, often with subsequent ulceration, and eventually healed with scarring. Forty-eight persons received antibiotic therapy (33 received dual-agent therapy and 15 received monotherapy). Thirteen persons were considered to be untreated; 11 received no antibiotics, and 2 were treated for!1 week. No persons required surgical resection of lesions. All treated and untreated persons eventually had resolution of disease. One initially untreated, HIV-negative person was given antibiotic therapy after lym- M. fortuitum Skin Infection CID 2004:38 (1 January) 39

3 Figure 1. Photograph of a typical boil lesion (size is specified in centimeters) 13 weeks after onset phatic dissemination of infection and the development of a large intrathigh abscess that required drainage. Samples of the abscess were obtained for culture, and culture results were positive for M. fortuitum. Persons who received antibiotics were treated for a mean duration of 4 months (range, 1 6 months). Clinicians most frequently used ciprofloxacin, doxycycline, or clarithromycin (table 1). Patients often changed drugs during the course of treatment because of side effects, cost, or other reasons. For instance, a person who was receiving monotherapy may have initially been treated with ciprofloxacin for 3 weeks, switched to doxycycline for 8 weeks, and then switched to minocycline for 10 weeks. It is notable that doxycycline or minocycline were the drugs most frequently administered to persons who received monotherapy (14 of 15 patients, including 12 who received only doxycycline or minocycline during their entire treatment course). Patients who were receiving dual-agent therapy underwent similar changes in drugs, and use of the second antibiotic was often intermittent. Ciprofloxacin was the most frequently employed drug in dual-agent therapy (31 of 33 patients), followed by clarithromycin (20 of 33 patients), and doxycycline or minocycline (17 of 33 patients). Thirty-two persons had culture-confirmed disease. Of the remaining patients, 16 did not undergo punch biopsy for culture, 3 had biopsy tissue specimens that were incorrectly processed and not cultured, and 10 had negative results of cultures of biopsy tissue specimens. Thirty isolates were identified as M. fortuitum, and 2 were rapidly growing mycobacteria that were not identified to the species level. Isolates were generally susceptible to amikacin, cefoxitin, ciprofloxacin, doxycycline, gentamicin, and minocycline and were resistant to sulfa, clarithromycin, azithromycin, and augmentin (table 2). Only 1 (3%) of the 32 positive biopsy tissue specimens had bacilli demonstrable on an acid-fast bacilli smear. Ten patients with culture-confirmed disease also had swabs of wound drainage submitted for mycobacterial culture, and 7 swab cultures were positive. Fifteen dermatopathological reports were submitted by treating physicians. Results of histopathological analysis of the lesions were variable and seemed to be consistent with the age of the lesion that was sampled by biopsy. Older lesions tended to demonstrate chronic inflammatory changes with few inflammatory cells present. More-acute lesions displayed granuloma formation, mixed inflammatory cell infiltrate, and local tissue destruction. Such inflammatory changes were often localized in or near the hair follicle. Mycobacteria were not seen in any of the specimens that underwent pathological analysis. Treated and untreated persons were similar with respect to the prevalence of culture-positive disease (50% vs. 61%, respectively) and the proportion who were receiving treatment from experienced providers (50% vs. 54%, respectively). However, treated persons had a higher number of boils than did untreated persons (mean, 4.7 vs. 2.3 boils; P p.07) and were significantly more likely to have multiple boils (OR, 3.5; 95% CI, ; P p.05). Clinical resolution and disease onset dates were both available for 56 persons (90%) for whom disease duration could be calculated. Overall, the mean disease duration was 170 days (range, days). By univariate analysis, disease duration was similar for treated and untreated groups (mean duration, 40 CID 2004:38 (1 January) Winthrop et al.

4 Figure 2. Photograph of lesion progression (size is specified in centimeters) after central drainage 14 weeks after onset 168 vs. 177 days, respectively). Persons with culture-negative disease and those for whom no culture was performed had a shorter disease duration than did those with positive culture results (mean duration, 136 vs. 198 days; P!.01). Persons treated by experienced providers had significantly shorter durations of disease (mean duration, 143 vs. 195 days; P!.01). Initiation of treatment earlier in the disease course was linearly and significantly associated with shorter mean disease duration ( P!.01). Having a single boil versus multiple lesions was also associated with a shorter mean disease duration (mean duration, 138 vs. 181 days; P p.04). Stratified analysis suggested that the effect of treatment might have differed according to the number of boils present. In persons with multiple boils ( n p 41), therapy showed a trend toward shorter disease duration, compared with untreated persons (mean duration, 173 vs. 231 days; P p.07). Among per- Figure 3. Photograph of lesion progression (size is specified in centimeters) at 17 weeks after onset M. fortuitum Skin Infection CID 2004:38 (1 January) 41

5 Figure 4. Photograph of boil resolution, with characteristic hyperpigmented macular scar, 10 months after onset sons with only a single boil, disease durations were similar in both treated and untreated groups (mean duration, 147 vs. 123 days; P p 0.50). A final, multivariable linear regression model controlling for the noted effects of culture result, physician experience, number of boils, and the interaction between the number of boils and treatment indicated that early initiation of antibiotic therapy (1 70 days after disease onset) was associated with shorter disease duration only in persons with multiple boils ( P!.01) (table 3). with antibiotic therapy in persons with a single lesion. Given that 14 of 19 patients with a solitary lesion also underwent skin punch biopsy, it might be that removal of infecting organisms during the biopsy hastened disease resolution without the aid of antibiotic therapy. Although surgical resection of lesions has been reported by other authors in the treatment of cutaneous infection caused by rapidly growing mycobacteria [8, 10], our experience indicates that oral antibiotic therapy alone may be sufficient for DISCUSSION We observed the clinical course of 61 persons with lowerextremity M. fortuitum furunculosis acquired from whirlpool footbaths at a nail salon. Of importance, we demonstrated that these infections can be treated effectively with oral antibiotic therapy and that surgical resection is not necessary. Our data suggest that persons with more extensive disease (i.e., 1 boil) who initiate antibiotic therapy early in the disease course benefit most from therapy. Although untreated infections can be selflimited in a healthy host, we found that lymphatic dissemination of infection can occur. Patients who present for evaluation early in their disease course in particular, those with multiple boils appear to be the best candidates for antibiotic therapy. Because these infections can be self-limited (at least in healthy hosts), initiation of antibiotic therapy late in the disease course might not significantly enhance immune system response to the infection. It is unclear why our analysis failed to find benefit associated Table 1. Antibiotic therapy administered to patients who were characterized as having received treatment. Antibiotic No. (%) of patients treated a (n p 48) Ciprofloxacin 34 (71) Doxycycline 22 (46) Clarithromycin 21 (44) Minocycline 12 (25) Azithromycin 7 (15) TMP-SMX 3 (6) Levofloxacin 3 (6) NOTE. The number of patients treated with each antibiotic in the table exceeds the overall number of persons treated in the study, because many persons were treated with 11 antibiotic throughout the disease course. TMP- SMX, trimethoprim-sulfamethoxazole. a See Patients and Methods for the distinction between treated and untreated patients. 42 CID 2004:38 (1 January) Winthrop et al.

6 Table 2. Results of antibiotic susceptibility testing of 29 isolates. Antibiotic Susceptible Intermediately susceptible or resistant Mode MIC, mg/ml MIC 90, mg/ml Amikacin 29 (100) 0 (0) 1 4 Ciprofloxacin 29 (100) 0 (0) Minocycline 10 (100) 0 (0).5.5 Cefoxitin 10 (91) 1 (9) Doxycyline 16 (89) 2 (11).25 2 Gentamicin 9 (82) 2 (18) 4 8 TMP-SMX 10 (61) 16 (39) Clarithromycin 4 (14) 25 (86) Azithromycin 1 (10) 9 (90) Erythromycin 1 (9) 11 (91) Augmentin 0 (0) 11 (100) NOTE. Data are no. (%) of isolates that underwent susceptibility testing, unless otherwise indicated. TMP-SMX, trimethoprim-sulfamethoxazole. treating salon-acquired infection caused by M. fortuitum. The optimal duration of antibiotic therapy is unknown. Our patients were treated for a mean duration of 4 months. Whether dual-agent therapy is more advantageous than monotherapy is also unknown. In addition to low numbers of study subjects and frequent drug switching by patients, our assessment of this question was further complicated by the fact that more than one-half of those who were treated with dual-agent therapy were, at times, being treated with clarithromycin, a drug to which most of the M. fortuitum isolates ultimately showed resistance. In such cases, those persons were probably effectively being treated with monotherapy. Clinicians could consider choosing dual-agent therapy to possibly prevent acquired drug resistance. Acquired fluoroquinolone resistance has been demonstrated previously with ciprofloxacin monotherapy for cutaneous M. fortuitum infection [11], and acquired clarithromycin resistance has been shown in the single-agent treatment of cutaneous infection caused by M. chelonae (another rapidly growing mycobacterium) [12]. Because most physicians in our study were aware of these reports, nearly all patients who were receiving monotherapy were treated with doxycycline or minocycline throughout all or most of the treatment course. The diagnosis of such infections can be challenging without clinical suspicion of mycobacterial etiology. Although M. fortuitum and related organisms will grow on standard blood agar culture media, they typically do so only after 3 7 days under ideal conditions [6, 13]. Therefore, cultures for routine organisms frequently fail to yield these mycobacteria, because they are typically not held long enough to demonstrate such growth. Mycobacteria may also be difficult to collect for culture, particularly if swab samples of wounds are used. Other authors have recommended the use of skin punch biopsies to capture organisms for culture, and we indeed found this procedure to be more sensitive than using swab samples of wounds [14]. Finally, acid-fast bacilli smears appear to have little utility for diagnosis, because only 1 person in our cohort had bacilli demonstrable on smear. Because our study was observational by design, our ability to draw firm conclusions regarding the utility of antibiotic therapy was limited. To determine disease duration, we relied on the subjective opinion of many different physicians. It is possible that the subjective assessment of disease resolution or patient follow-up frequencies may have varied between physicians, depending on disease severity, treatment group, or some other variables associated with clinical expertise or training. We attempted to control for this by including a physician variable in our model. We were also limited in our ability to assess outcomes other than disease duration. Although all lesions were noted to result in scarring, we could not assess whether antibiotics mitigated this outcome. In summary, clinicians should consider rapidly growing mycobacteria in the differential diagnosis of any difficult-to-treat soft-tissue infection, particularly when the infection is associated with whirlpool footbaths commonly used in nail salons. Of importance, we have demonstrated that M. fortuitum furunculosis can be treated successfully with oral antibiotic therapy in otherwise healthy persons and that surgical therapy is not necessary. Our experience suggests that persons in particular, those with multifocal disease benefit most from treatment initiated early in the disease course. Although untreated infection may be self-limited, dissemination of these infections can occur among healthy individuals, and persons who are untreated should be observed closely for such complications. The risk of disease reactivation is unknown, but, at the time of writing, no persons in this study have reported recurrence of disease. Acknowledgments We thank Dr. Genevieve Ashcom, Dr. James Beckett, Dr. Lorena Bischoff, Dr. Andrew Calciano, Dr. Mitra Choudri, Dr. Table 3. Disease duration, by treatment group, in persons with multiple boils at presentation to the treating physician. Treatment group, days a No. of patients Disease duration, mean days (range) None ( ) Reference group (45 317)! ( )! ( ).44 a Interval between disease onset and initiation of treatment. b By multivariate modeling. P b M. fortuitum Skin Infection CID 2004:38 (1 January) 43

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