ABSTRACT
Nocardia species cause a broad spectrum of infections, especially in immunocompromised patients. Given its relative rarity, data on the prognosis and distribution of nocardiosis from a large cohort are scarce. The present study aimed to scrutinize the clinical features and outcomes of nocardiosis in Japan, including 1-year mortality and microbiological data. The present multicentric, retrospective cohort study enrolled patients aged ≥18 years with nocardiosis diagnosed between January 2010 and December 2017 and recorded their clinical and microbiological characteristics. Factors associated with 1-year mortality were also determined using Cox proportional hazard analysis. In total, 317 patients were identified at 89 hospitals. Almost half (155/317, 48.9%) were receiving immunosuppressive agents, and 51 had disseminated nocardiosis (51/317, 16.1%). The 1-year all-cause mortality rate was 29.4% (80/272; lost to follow-up, n = 45). The most frequently isolated species was Nocardia farcinica (79/317, 24.9%) followed by the Nocardia nova complex (61/317, 19.2%). Selected antimicrobial agents were generally effective, with linezolid (100% susceptibility [S]) and amikacin (94% S) having the most activity against Nocardia species. In Cox proportional hazard analysis, factors independently associated with 1-year mortality were a Charlson comorbidity index score of ≥5 (adjusted hazard ratio [aHR], 3.61; 95% confidence interval [CI], 1.95 to 6.71, P < 0.001) and disseminated nocardiosis (aHR, 1.79; 95%CI, 1.01 to 3.18, P = 0.047). The presence of advanced comorbidities and disseminated infection, rather than variations in antimicrobial therapy or Nocardia species, was independently associated with 1-year mortality.
KEYWORDS: Nocardia, nocardiosis, 1-year mortality, antimicrobial susceptibilities
INTRODUCTION
Nocardia species are ubiquitous, environmental, Gram-positive, branching, beaded, aerobic, filamentous bacteria which cause severe opportunistic infections in humans (1). Cases of human nocardiosis have increased over the last several decades (2) in association with an increasing number of immunocompromised hosts and progress in diagnostics and identification of Nocardia species in laboratories (3). Nocardiosis usually arises from direct inoculation via the skin, soft tissues, or inhalation leading to chronic, indolent skin infections or pulmonary nodules, mainly in patients with impaired cell-mediated immunity (1). The most common infection site is the lung (1); however, disseminated nocardiosis may also occur via hematogenous spread with lethal consequences.
Case series of Nocardia infections are often limited by small sample sizes and a focus on specific populations, such as solid organ transplant recipients and cancer patients (4–6), or specific clinical manifestations, such as pulmonary nocardiosis or central nervous system (CNS) nocardiosis (7–9). Although a number of small-scale studies of nocardiosis focusing on its clinical epidemiology have been published in various countries (10–15), few large-population studies integrating clinical data with microbiological characteristics of Nocardia species have been done. Moreover, few studies have examined the risk factors associated with mortality in patients with nocardiosis using an appropriate methodology (4, 16, 17).
The present study aimed to scrutinize the clinical characteristics, outcomes, and distribution of nocardiosis throughout Japan while also investigating the predictors of 1-year mortality using comprehensive clinical and microbiological data on a nocardiosis cohort.
RESULTS
Clinical characteristics of the participants.
During the study period, 576 clinical samples were sent to the Medical Mycology Research Center (MMRC), and 89 hospitals agreed to participate, leaving 317 patients for analysis. Table 1 shows their clinical characteristics; their median age was 71 years (interquartile range [IQR], 60 to 78), with males accounting for 55.2% (175/317) of the cohort. Almost half (155/317, 48.9%) of the patients had received immunosuppressants recently or at the time of nocardiosis development. The most common infection site was the lungs (218/317, 68.8%) followed by skin (41/317, 12.9%). Table S2 in the supplemental material shows the symptoms associated with nocardiosis. Two hundred seven patients (207/317, 65.3%) presented with respiratory symptoms (cough, sputum, dyspnea, hemoptysis, or chest pain), and 56 patients (56/317, 17.7%) presented with symptoms consistent with central nervous system (CNS) involvement (disturbance of consciousness, headache, paralysis, other neurological deficits, or visual disturbance). Disseminated infections occurred in 51 patients (51/317, 16.1%); of these, 52.9% (27/51) had CNS involvement. The proportion of patients with immunosuppressant use (35/51, 68.6% versus 120/266, 45.1%) and nocardiosis due to Nocardia farcinica (28/51, 54.9% versus 51/266, 19.2%) was greater in the disseminated infection group than in the localized nocardiosis group.
TABLE 1.
Characteristics of patients with nocardiosisa
| Variable | Data for: |
P value | ||
|---|---|---|---|---|
| Total (n = 317) | Disseminated infection (n = 51) | Localized infection (n = 266) | ||
| Patient demographics | ||||
| Age (median [IQR] [yrs]) | 71 (60–78) | 69 (57–79) | 71 (60–78) | 0.584 |
| ≥65 (no. [%]) | 209 (65.9) | 29 (56.9) | 180 (67.7) | 0.136 |
| Male sex (no. [%]) | 175 (55.2) | 34 (66.7) | 141 (53.0) | 0.072 |
| Asian race (no. [%]) | 315 (99.4) | 51 (100) | 264 (99.3) | 0.534 |
| History of smoking (no. [%]) | 115 (36.3) | 22 (43.1) | 93 (35.0) | 0.266 |
| Habitual alcohol use (no. [%]) | 86 (27.1) | 16 (31.4) | 70 (26.3) | 0.457 |
| Comorbidities (no. [%]) | ||||
| Chronic lung disease | 105 (33.1) | 7 (13.7) | 98 (36.8) | 0.001 |
| Active malignancy | 49 (15.5) | 7 (13.7) | 42 (15.8) | 0.709 |
| Diabetes mellitus | 78 (24.6) | 13 (25.5) | 65 (24.4) | 0.873 |
| Chronic liver disease | 26 (8.2) | 7 (13.7) | 19 (7.1) | 0.117 |
| Chronic kidney disease | 61 (19.2) | 10 (19.6) | 51 (19.2) | 0.942 |
| HIV infection | 6 (1.9) | 1 (2.0) | 5 (1.9) | 1.000 |
| Charlson comorbidity index score (median [IQR]) | 4 (3–6) | 4 (3–6) | 4 (3–6) | 0.755 |
| History of solid organ transplantation (no. [%]) | 3 (0.9) | 1 (2.0) | 2 (0.8) | 0.410 |
| History of hematological transplantation (no. [%]) | 14 (4.4) | 3 (5.9) | 11 (4.1) | 0.478 |
| Immunosuppressant use in the last 28 days (no. [%]) | 155 (48.9) | 35 (68.6) | 120 (45.1) | 0.002 |
| Systemic corticosteroid only (no. of patients/total no. of patients with immunosuppressant use [%]) | 80/155 (51.6) | 16/35 (45.7) | 64/120 (53.3) | |
| Systemic corticosteroid and other agents (no. of patients/total no. of patients [%]) | 70/155 (45.2) | 19/35 (54.3) | 51/120 (42.5) | |
| Other agents only (no. of patients/total no. of patients [%]) | 5/155 (3.2) | 0 (0) | 5/120 (4.2) | |
| Prophylactic use of TMP-SMX (no. [%]) | 46 (14.5) | 10 (19.6) | 36 (13.5) | 0.259 |
| Prophylactic use of antiviral agent for CMV (no. [%]) | 7 (2.2) | 4 (7.8) | 3 (1.1) | 0.014 |
| Prophylactic use of antifungal agent (no. [%]) | 32 (10.1) | 4 (7.8) | 28 (10.5) | 0.800 |
| Nocardiosis due to N. farcinica (no. [%]) | 79 (24.9) | 28 (54.9) | 51 (19.2) | <0.001 |
| Treatment and management of nocardiosis | ||||
| Initial treatment (no. [%]) | 0.082 | |||
| Monotherapy | 236 (74.4) | 33 (64.7) | 203 (76.3) | |
| Combination therapy | 81 (25.6) | 18 (35.3) | 63 (23.7) | |
| Resistance to TMP-SMX (no. [%]) | 73 (23.0) | 17 (33.3) | 56 (21.0) | 0.056 |
| Median no. of antimicrobial agents (both oral and intravenous) showing resistance per isolate with susceptibility criteria (IQR)b | 6 (4–8) | 8 (6–9) | 6 (4–8) | <0.001 |
| Change in antimicrobial agent based on susceptibility test results (no. [%]) | 97 (30.9) | 18 (35.3) | 79 (30.0) | 0.457 |
| Surgical intervention for nocardiosis (no. [%]) | 43 (13.6) | 16 (31.4) | 27 (10.2) | <0.001 |
| Abscess incision and drainage (no./total no. with surgical intervention [%]) | 19/43 (44.2) | 4/16 (25) | 15/27 (55.6) | |
| Neurosurgery (no./total no. with surgical intervention [%]) | 10/43 (23.3) | 10/16 (62.5) | 0/27 (0) | |
| Thoracic surgery (no./total no. with surgical intervention [%]) | 8/43 (18.6) | 1/16 (6.3) | 7/27 (25.9) | |
| Orthopedic surgery (no./total no. with surgical intervention [%]) | 4/43 (9.3) | 0/16 (0) | 4/27 (14.8) | |
| Other (no./total no. with surgical intervention [%]) | 2/43 (4.7) | 1/16 (6.3) | 1/27 (3.7) | |
| ICU stay for nocardiosis (no. [%]) | 14 (4.4) | 8 (15.7) | 6 (2.3) | <0.001 |
| Infectious disease consultation (no. [%]) | 139 (43.8) | 28 (54.9) | 111 (41.7) | 0.082 |
| Duration of treatment (median [IQR] [days]) (n = 296; n = 21 lost to follow-up) | 170 (47–356) | 222 (56–389) | 159 (48–328) | 0.188 |
Abbreviations: IQR, interquartile range; HIV, human immunodeficiency virus; TMP-SMX, trimethoprim-sulfamethoxazole; CMV, cytomegalovirus; ICU, intensive care unit.
Includes both intermediate and resistant.
Nocardia species and their antimicrobial susceptibility.
Table 2 shows that the most frequently isolated species were N. farcinica (79/317, 24.9%), N. nova complex (61/317, 19.2%), N. abscessus complex (59/317, 18.6%), and N. cyriacigeorgica (44/317, 13.9%). Antimicrobial susceptibility profiles, according to CLSI M24-A (18), varied widely among the species. Selected antimicrobials were generally very effective, with linezolid (100% susceptibility [S]) and amikacin (94% S) showing the strongest activity; 77% and 80% of the isolates were susceptible to trimethoprim-sulfamethoxazole (TMP-SMX) and imipenem-cilastatin, respectively.
TABLE 2.
Antimicrobial susceptibility profile by Nocardia species (n = 317)
| Antimicrobial agent | No. (%) of susceptible isolates of: |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| All Nocardia isolates (n = 317) | N. nova complex (n = 61) | N. abscessus complex (n = 59) | N. transvalensis complex (n = 15) | N. farcinica (n = 79) | N. cyriacigeorgica (n = 44) | N. brasiliensis (n = 23) | N. exalbida (n = 10) | Other Nocardia speciesa (n = 26) | |
| Amikacin | 298 (94.0) | 61 (100) | 59 (100) | 0 (0) | 79 (100) | 44 (100) | 23 (100) | 10 (100) | 22 (84.6) |
| Amoxicillin-clavulanic acid | 182 (57.4) | 5 (8.2) | 33 (55.9) | 14 (93.3) | 79 (100) | 18 (40.9) | 23 (100) | 1 (10) | 9 (34.6) |
| Ceftriaxone | 172 (54.3) | 39 (63.9) | 55 (93.2) | 11 (73.3) | 5 (6.3) | 40 (90.9) | 2 (8.7) | 10 (100) | 10 (38.5) |
| Ciprofloxacin | 54 (17.0) | 1 (1.6) | 6 (10.2) | 7 (46.7) | 34 (43.0) | 1 (2.3) | 0 (0) | 0 (0) | 5 (19.2) |
| Imipenem-cilastatin | 255 (80.4) | 60 (98.3) | 48 (81.4) | 5 (33.3) | 72 (91.1) | 44 (100) | 5 (21.7) | 10 (100) | 11 (42.3) |
| Linezolid | 317 (100) | 61 (100) | 59 (100) | 15 (100) | 79 (100) | 44 (100) | 23 (100) | 10 (100) | 26 (100) |
| Minocycline | 138 (43.5) | 21 (34.4) | 46 (78.0) | 5 (33.3) | 24 (30.4) | 15 (34.1) | 8 (34.8) | 6 (60) | 13 (50) |
| Trimethoprim-sulfamethoxazole | 244 (77.0) | 53 (86.9) | 59 (100) | 8 (53.3) | 37 (46.8) | 41 (93.2) | 21 (91.3) | 9 (90) | 16 (61.5) |
| Tobramycin | 158 (49.8) | 2 (3.3) | 58 (98.3) | 0 (0) | 2 (2.5) | 43 (97.7) | 23 (100) | 10 (100) | 20 (76.9) |
| Cefotaxime | 174 (54.9) | 40 (65.6) | 58 (98.3) | 11 (73.3) | 6 (7.6) | 37 (84.1) | 3 (13.0) | 10 (100) | 9 (34.6) |
| Cefepime | 178 (56.2) | 49 (80.3) | 55 (93.2) | 11 (73.3) | 6 (7.6) | 36 (81.8) | 2 (8.7) | 10 (100) | 9 (34.6) |
| Doxycycline | 66 (20.8) | 1 (1.6) | 35 (59.3) | 1 (6.7) | 4 (5.1) | 8 (18.2) | 5 (21.7) | 2 (20) | 10 (38.5) |
| Gentamicin | 155 (48.9) | 12 (19.7) | 43 (72.9) | 0 (0) | 1 (1.3) | 43 (97.7) | 23 (100) | 10 (100) | 23 (88.5) |
| Clarithromycin | 91 (28.7) | 59 (96.7) | 15 (25.4) | 1 (6.7) | 0 (0) | 2 (4.5) | 0 (0) | 1 (10) | 13 (50) |
N. otitidiscaviarum (n = 8), N. pseudobrasiliensis (n = 4), N. puris (n = 3), N. concave (n = 2), N. vinacea (n = 2), N. araoensis (n = 1), N. mexicana (n = 1), N. terpenica (n = 1), N. thailandica (n = 1), N. yamanashiensis (n = 1), N. paucivorans (n = 1), Nocardia spp. (n = 1).
Treatment and management of nocardiosis.
Two hundred thirty-six patients (236/317, 74.4%) received monotherapy as their initial treatment (Table 1), the details of which are shown in Table S3. Forty-three patients (43/317, 13.6%) underwent surgery for nocardiosis, and 139 patients (139/317, 43.8%) received an infectious disease consultation. The median duration of antimicrobial therapy was 170 days (IQR, 47 to 356). The proportion of patients with surgical intervention (16/51, 31.4% versus 27/266, 10.2%) and intensive care unit admission (8/51, 15.7% versus 6/266, 2.3%) was higher in the disseminated infection group than in the localized infection group. Instances of antimicrobial resistance were also more numerous among patients with a disseminated infection (8 [IQR, 6 to 9] versus 6 [IQR, 4 to 8]). Adverse drug events during treatment occurred in 47.3% of the patients (150/317). The discordance rate between initial antimicrobial therapy and antimicrobial susceptibility in the isolated pathogens in patients with disseminated nocardiosis was 54.5% (18/33) in the monotherapy group and 5.6% (1/18) in the combination therapy group.
Outcomes and risk of 1-year mortality.
Relapses occurred in 12.5% of the patients (36/288; lost to follow-up, n = 29). One-year all-cause mortality was 29.4% (80/272; lost to follow-up, n = 45). Table S4 shows all-cause mortality within 365 days stratified by Nocardia species. Figure 1 shows the Kaplan-Meier survival curve for 1-year mortality in patients with nocardiosis. Patients with nocardiosis who died within a year after diagnosis were more likely to be elderly. In the Cox proportional hazard model, factors independently associated with 1-year mortality were a Charlson comorbidity index score of ≥5 (adjusted hazard ratio [aHR], 3.61; 95% confidence interval [CI], 1.95 to 6.71, P < 0.001) and disseminated nocardiosis (aHR, 1.79; 95% CI, 1.01 to 3.18, P = 0.047) (Table 3). Neither resistance to trimethoprim-sulfamethoxazole nor infection due to N. farcinica was associated with 1-year mortality.
FIG 1.
One-year Kaplan-Meier survival curves of patients with nocardiosis from the initiation of treatment. (A) Overall (n = 317). (B) Stratified by Charlson comorbidity index score. The adjusted hazard ratio for 1-year mortality was 3.61 (P < 0.001). (C) Stratified by infection site. The adjusted hazard ratio for 1-year mortality was 1.79 (P = 0.047).
TABLE 3.
Risk factors associated with 365-day all-cause mortalitya
| Variableb | Crude HR (95% CI) | P value | Adjusted HR (95% CI) | P value |
|---|---|---|---|---|
| Old age (≧65 years) | 1.93 (1.14–3.25) | 0.014 | 0.96 (0.51–1.82) | 0.904 |
| History of chronic lung disease | 1.35 (0.86–2.11) | 0.193 | 1.40 (0.85–2.30) | 0.186 |
| Charlson comorbidity index score > 4 | 4.15 (2.52–6.83) | <0.001 | 3.61 (1.95–6.71) | <0.001 |
| Immunosuppressant use in the previous 28 days | 2.18 (1.38–3.45) | 0.001 | 1.58 (0.95–2.63) | 0.076 |
| Nocardiosis due to N. farcinica | 1.48 (0.93–2.36) | 0.100 | 0.79 (0.45–1.38) | 0.405 |
| Disseminated nocardiosis | 1.67 (0.99–2.82) | 0.057 | 1.79 (1.01–3.18) | 0.047 |
| Resistance to TMP-SMX | 1.63 (1.02–2.61) | 0.043 | 1.40 (0.81–2.39) | 0.225 |
| No. of antimicrobial agents showing resistance per isolate with susceptibility criteria > 4 | 1.30 (0.79–2.16) | 0.303 | 1.07 (0.61–1.89) | 0.806 |
Abbreviations: HR, hazard ratio; CI, confidence interval; TMP-SMX, trimethoprim-sulfamethoxazole.
Variables of interest (history of chronic lung disease, immunosuppressant use, number of antimicrobial agents showing resistance per isolate with susceptibility criteria, disseminated nocardiosis), variables associated with mortality identified in previous studies (age, nocardiosis due to N. farcinica, resistance of TMP-SMX), and variables with a P value of <0.1 on bivariable analysis with clinical plausibility (Charlson comorbidity index score) were considered for inclusion in the final models.
DISCUSSION
The present study was one of the most extensive cohort studies to describe both the clinical and microbiological characteristics of nocardiosis over a 7-year period. In line with other studies (4, 16), pulmonary nocardiosis was the most common type of clinical infection. Diversity in the distribution of Nocardia species and their various susceptibilities to the antimicrobials commonly used for nocardiosis were also observed. Moreover, the present study demonstrated that a high Charlson comorbidity index score and disseminated nocardiosis were independent predictors of 1-year mortality in patients with nocardiosis.
It is noteworthy that disseminated nocardiosis resulted in substantial mortality. The 1-year mortality rate varied by study population, with ∼16.2% to 38.2% reported in previous studies and 29% reported in the present study (4, 10, 19). One possible reason for this higher mortality rate may be the inadequacy of the initial antimicrobial therapy. In our cohort, nearly two-thirds of patients with disseminated nocardiosis received monotherapy as their initial regimen, and over half of those receiving monotherapy later showed a discordance between the initial antimicrobial therapy and antimicrobial susceptibility in the isolated pathogens. Although data on differences in the efficacy of monotherapy versus combination antimicrobial therapy are scarce, combination therapy is preferable for severe infections, including disseminated nocardiosis (20, 21). Moreover, since disseminated nocardiosis is commonly accompanied by CNS lesions (e.g., brain abscesses) (1), administrating antimicrobial agents capable of penetrating the CNS and performing adequate surgical intervention to manage the infection foci are vital to achieving a cure and reducing mortality (9, 22). Given the high rate of mortality associated with disseminated infections, combination antimicrobial therapy is recommended until the antimicrobial susceptibilities and optimal surgical management can be determined.
Our study demonstrated that the presence of advanced comorbidities (i.e., high Charlson comorbidity index) was an independent predictor of mortality. Although it is unclear which underlying illness most influenced the mortality rate, it is important to recognize that the presence of advanced comorbidities has the potential to predict the prognosis of nocardiosis.
To date, more than 200 Nocardia species have been cataloged in the List of Prokaryotic Names with Standing in Nomenclature (https://lpsn.dsmz.de/search?word=nocardia). Previous studies demonstrated that the distribution of Nocardia species varied geographically; for example, the predominant species by region were N. nova complex in the United States and Australia (12, 15, 23, 24), N. cyriacigeorgica in Spain (25), and N. farcinica in China and France (14, 26). In this cohort in Japan, the most frequently isolated species was N. farcinica. Although the differences in the distribution of Nocardia are not clearly understood, climate conditions may play a role (1). Interestingly, the mortality rate differed by species. For instance, previous studies demonstrated poor outcomes in patients with nocardiosis due to N. farcinica, and a similar trend was observed in the present study, although it did not reach statistical significance (16, 27). The findings of the present study demonstrated that disseminated nocardiosis was independently associated with mortality. Moreover, N. farcinica, which had lower antimicrobial susceptibility, accounted for 55% of all disseminated nocardiosis cases (N. farcinica group, 54.9% [28/51], versus non-N. farcinica group, 45.1% [23/51], in our study). These findings were also supported by Munoz et al. (27). Thus, we believe that the difference in the proportion of species in disseminated nocardiosis leading to lower antimicrobial susceptibility patterns might explain the difference in the mortality rate associated with the disease. Identifying Nocardia species is challenging due to the inherent difficulty of recovering the organisms but is clinically important given the species-dependent differences in outcomes and antimicrobial susceptibility (3). Moreover, since antimicrobial susceptibility patterns differ by the Nocardia species, understanding the geographical distribution of Nocardia species may enable us to determine which empirical antimicrobial agents are best able to minimize the so-called drug-bug mismatch until the species with antimicrobial susceptibilities can be identified precisely.
TMP-SMX was most often administered as the initial therapy in the present study. Given its good in vitro activity against Nocardia, TMP-SMX is recommended as one of the first-line agents against the disease (20, 21). However, TMP-SMX-resistant strains have been reported, and other agents, including linezolid, imipenem-cilastatin, and amikacin, have demonstrated better activity against almost all Nocardia species, as seen in the current study (23, 26). Linezolid, an oxazolidinone antimicrobial with excellent activity against Nocardia species, can be safely administered as the initial therapy with other agents (28). Linezolid also has the advantage of being available in both an intravenous and oral form as well as having the ability to penetrate the CNS. Since nearly half of the patients in our study experienced some form of adverse drug reaction during treatment, toxicity resulting from the prolonged use of antimicrobials, especially linezolid, TMP-SMX, or amikacin, is a concern. Therefore, its risks and benefits should be weighed against those of other regimens, especially in severe cases, cases where antimicrobial choice is limited due to multidrug resistance or where antimicrobial use is contraindicated (e.g., because of an allergy or other potential adverse events).
The present study has several limitations. First, because it retrospectively analyzed patient data in medical records, the frequency of some clinical variables may have been underestimated. Further, 1-year mortality was unknown in 14% (45/317) of the patients due to loss to follow-up. Second, the impact of definitive antimicrobial therapy and its impact on patient mortality was not assessed because data on definitive antimicrobial therapy after antimicrobial susceptibility testing were often missing, presumably from loss to follow-up after hospital discharge. Changes in antimicrobial regimens also frequently occurred, presumably in response to adverse drug events or intolerance. Additionally, the impact of the duration of therapy was unable to be assessed because deceased patients had a shorter duration of therapy due to death, which may have caused an information bias. Moreover, the impact of the initial choice of antimicrobial agent and the effect of discordant antimicrobial therapy on mortality was unable to be assessed. However, since antimicrobial therapy was modified based on susceptibility results in 30% of the patients, it may be hypothesized that the initial antimicrobial therapy might have been inadequate in a certain portion of the cohort. Third, because the factors associated with all-cause mortality were investigated, the results may not represent mortality directly attributable to nocardiosis. Last, even after adjusting for known predisposing factors, other, unmeasured factors may have contributed to the 1-year mortality rate.
In conclusion, nocardiosis is still a challenging infectious disease requiring long-term antimicrobial therapy and is associated with a substantial risk of mortality. The current study demonstrated the geographical distribution and susceptibility patterns of Nocardia species in Japan and found that the presence of advanced comorbidities and disseminated infection were nonmodifiable, independent predictors of 1-year mortality. These findings suggest the need to understand the microbiology of nocardiosis better so that antimicrobial therapy can be optimized and appropriate surgical intervention be performed, if necessary, to prevent unfavorable outcomes.
MATERIALS AND METHODS
Study design and setting.
The present study was a multicentric retrospective cohort study conducted in Japan. The Medical Mycology Research Center (MMRC) at Chiba University, located in Chiba, Japan, serves as a central laboratory providing microbiological analysis of Nocardia species to help guide therapeutic decisions in patients with nocardiosis. Tokyo Metropolitan Tama Medical Center (TMTMC), a public tertiary care center located in Tokyo, Japan, is one of the hospitals supplying clinical samples of suspected Nocardia infections to the MMRC. The infectious diseases physicians at TMTMC created a clinical data collection, and the researchers at the MMRC performed the final identification, susceptibility testing, and preservation of the organisms through the National Bio-Resource Project (http://www.nbrp.jp/).
Participants.
A list of potentially eligible patients was obtained from the clinical sample lists of the MMRC. The primary investigators recruited investigators at each site who were tasked with treating the patients after they submitted the patients’ clinical information and completed their data collection form.
The inclusion criteria were (i) clinical samples of Nocardia species sent to the MMRC for investigation between January 2010 and December 2017, (ii) age ≥18 years, and (iii) presence of signs or symptoms compatible with nocardiosis. The exclusion criteria were (i) cases imported from outside Japan, (ii) age <18 years, and (iii) Nocardia species isolated from clinical samples but unlikely to be the cause of a clinical infectious disease (e.g., colonization). The institutional review board (IRB) at TMTMC, Chiba University, and the other participating institutions approved this study. The patients’ consent was waived because the present study had no effect on managing the patients enrolled.
Data collection and definitions.
Detailed data on demographic characteristics, underlying morbidities, clinical presentations, sites of infection, treatment details, and clinical outcomes were retrospectively extracted from the medical records at each participating hospital. Microbiological data, including the identities of the Nocardia species and their antimicrobial susceptibility, were obtained from the MMRC. The clinical data collected from each site and the microbiological data from the MMRC were subsequently combined to form a complete cohort.
Habitual alcohol use was defined as the current alcohol intake documented in the medical records. Active malignancy was defined as any malignancy currently being treated, and systemic corticosteroid use was defined as a minimum of 5 mg/day prednisone for at least the previous 28 days. Immunosuppressants included systemic corticosteroids, calcineurin inhibitors, antimetabolites, alkylating agents, immunomodulatory agents, biologics, and other antineoplastic agents in the previous 28 days. Nocardiosis sites were categorized as (i) localized infections with one organ involvement, or (ii) disseminated infections (i.e., involving ≥2 noncontiguous organs, CNS involvement, or the presence of Nocardia species in blood culture samples) (10). Adverse drug events associated with antimicrobial use included anaphylactic reaction, rash, acute kidney injury, abnormal liver function test, hematological abnormalities, neurological abnormalities, gastrointestinal upset, and other events documented in the medical records. Relapse was defined as the association of clinical and radiological signs of nocardiosis with isolation of the same Nocardia species found at the initial diagnosis after discontinuation of antimicrobial treatment for nocardiosis (4). Follow-up data from a period up to 1 year after the initiation of treatment in the patients’ medical records were analyzed to assess the mortality rate.
Identification of Nocardia species and antimicrobial susceptibility.
Molecular identification of the isolated organisms was done with 16S rRNA PCR and phylogenetic analysis as described by Kageyama et al. (29). DNA sequences were determined using an automatic sequence analyzer (ABI Prism 3310; PE Applied Biosystems) with the BigDye Terminator cycle sequencing ready reaction kit (PE Applied Biosystems). Sequencing analysis of the 16S rRNA genes identified Nocardia species based on similarities with the reference sequence in GenBank (DDBJ/GenBank/EMBL) using BLAST (http://www.ncbi.nlm.nih.gov/BLAST/).
The antimicrobial susceptibility of the isolates was assessed by broth microdilution according to the Clinical and Laboratory Standard Institute (CLSI) guidelines M24-A (18). Susceptibility was determined by 80% inhibitory control. Table S1 in the supplemental material shows the antimicrobials used and the susceptibility breakpoints. Microtiter plates (dry plate; Eiken Chemicals, Tokyo, Japan) containing lyophilized antimicrobials were used after serial 2-fold dilution. The inoculum suspension was adjusted to 104 CFU/mL in Mueller-Hinton broth (0.2% beef extract, 1.75% casein hydrolysate, and 0.15% starch, pH 7.3), added to the microtiter wells in 0.1-mL aliquots and then incubated at 35°C. The growth control included the same inoculum without the antimicrobials, while the negative control was a sterile Mueller-Hinton broth. Visual examination of growth inhibition was performed at 72 h.
Statistical analysis.
Categorical variables were presented as a number and percentage, and continuous variables were presented as the median (interquartile range [IQR]). In univariate analysis, categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate, and continuous variables were compared using the Mann-Whitney U test. The primary outcome was 1-year survival after the initiation of nocardiosis treatment. Follow-up time was calculated from the initiation of treatment until either the date of death within 1 year or censoring. Survival was assessed using Kaplan-Meier survival curves. Cox proportional hazard analysis was performed to determine the hazard ratios (HRs) of 1-year mortality. Variables of interest, those associated with mortality identified in previous studies (4, 16, 17), and those with a P value of <0.1 on bivariate analysis with clinical plausibility were considered for inclusion in the final models. The proportional hazard assumption was assessed via -ln-ln survival curves and examined using Schoenfeld residuals. All tests for significance were two-tailed, with P values of <0.05 considered to indicate statistical significance, and 95% confidential intervals (CIs) were calculated. All the analyses were performed using Stata version 16 (StataCorp., College Station, TX, USA).
ACKNOWLEDGMENTS
We are indebted to James R. Valera for his assistance with editing the manuscript. We thank all of the following on-site investigators who registered data in the Japan Nocardia Study Group: Yasuo Takiguchi (Chiba Aoba Municipal Hospital), Tamon Yagi (Japanese Red Cross Musashino Hospital), Masaru Amishima (Hokkaido Medical Center), Noritaka Sekiya (Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital), Meiwa Shibata (Yokohama Rosai Hospital), Ryota Hase (Japanese Red Cross Narita Hospital), Yoshihiro Kobashi (Kawasaki Medical School), Akira Nakamura (Asahi General Hospital), Katsushi Tajima (Yamagata Prefectural Central Hospital), Nobuaki Mori (National Hospital Organization Tokyo Medical Center), Takashi Ishiguro (Saitama Cardiovascular and Respiratory Center), Takeaki Sugawara (Chiba Cancer Center), Hiroki Tateno (Saitama City Hospital), Nobuhiro Kodama (Fukuoka Tokushukai Hospital), Masaru Ando (Oita University Faculty Of Medicine), Hironori Uruga (Toranomon Hospital), Yoshifumi Uwamino (Keio University), Yukimasa Ooi (Osaka Medical College), Hanako Kurai (Shizuoka Cancer Center), Takuya Washino (Tokyo Metropolitan Bokutoh Hospital), Akihiro Toguchi (Kameda General Hospital), Toshimasa Hayashi (Maebashi Red Cross Hospital), Akihiro Sato (Tokyo Medical University Ibaraki Medical Center), Yukari Shimizu (Kumamoto Rosai Hospital), Hirokazu Toyoshima (Japanese Red Cross Ise Hospital), Takeshi Kinjo (University of the Ryukyus Hospital), Kazuhiro Asada (Shizuoka General Hospital), Toshimi Oda (Showa General Hospital), Kazuhito Saito (Tsuchiura Kyodo General Hospital), Kei Nakamura (Urasoe General Hospital), Kenji Kubo (Department of Emergency Medicine and Department of Infectious Diseases, Japanese Red Cross Wakayama Medical Center), Yoichi Tagami (National Defense Medical College Hospital), Yuji Miyoshi (Tokyo Metropolitan Health and Hospitals Corporation Tama-Hokubu Medical Center), Kenji Inoue (Japanese Red Cross Ishinomaki Hospital), Takeaki Nishibori (Japanese Red Cross Society Nagaoka Red Cross Hospital), Ken Tsutsumi (St. Marianna University School of Medicine), Tomokazu Kuchibiro (Naga Municipal Hospital), Yuka Ono (Mitsui Memorial Hospital), Akihiko Suganuma (Shin Koga Hospital), Kentaro Okuda (Ebara Hospital), Toshiki Furukawa (Niigata Prefectural Central Hospital), Masahiro Kobayashi (Ibarakihigashi National Hospital), Yohei Kanzawa (Akashi Medical Center), Haruka Ando (Showa University Fujigaoka Hospital), Yuriko Ichikawa (Nakadori General Hospital), Nobumasa Okumura (Anjo Kosei Hospital), Takehito Kobayashi (Tokyo Medical University Hospital), Yoichi Ohtake (Sakai City Medical Center), Naofumi Chinen (Tokyo Metropolitan Health and Hospitals Corporation Tama-Nambu Chiiki Hospital), Hiroshi Morioka (Nagoya University Hospital), Miwa Iio (Saiseikai Kumamoto Hospital), Akihiro Ueda (Japanese Red Cross Medical Center), Takeshi Nakazawa (Juntendo University School of Medicine Urayasu Hospital), Takahiro Matsuo (St. Luke's International Hospital), Hideki Koketsu (University of Miyazaki), Tatsuya Saito (Jichi Medical University Hospital), Kenji Sakamoto (Yamaguchi-Ube Medical Center), Nobujiro Abe (Self-Defense Forces Central Hospital), Takahiro Hosokawa (Gifu Prefectural General Medical Center), Ikkou Higashimoto (Kagoshima City Hospital), Fumihiro Ochi (Ehime University), Naofumi Kameyama (Sano Kosei General Hospital), Shinya Tomari (Isahaya General Hospital), Mari Yamamoto (Chubu Rosai Hospital), Yasushi Shibue (Yokohama City Minato Red Cross Hospital), Kazuya Iwai (Shizuoka City Shizuoka Hospital), Ryota Kominami (National Hospital Organization Himeji Medical Center), Satoshi Kimura (Showa University Northern Yokohama Hospital), Shinji Iyama (Kumamoto University Hospital), Mika Shiotsuka (National Cancer Center Japan), Masamitsu Ishihara (Holy Spirit Hospital), Nanako Tsutsui (Niigata Rinko Hospital), Hirokazu Tojima (Japan Labor Health and Safety Organization, Tokyo Rosai Hospital), Hiroyuki Kouzai (Tokushima University), Tatsuo Kato (National Hospital Organization Nagara Medical Center), Akira Iwashima (Nagaoka Central General Hospital), Akiko Ando (Sanjou General Hospital), Kenya Sumitomo (Division of Internal Medicine, Japan Agricultural Cooperatives Kochi Hospital), Takafumi Okada (Shikoku Medical Center for Children and Adults), Takehito Fusegawa (Saitama Citizens Medical Center), Toshiyuki Harada (JCHO Hokkaido Hospital), Kazuhiro Usui (NTT Medical Center Tokyo), Tamayo Watanabe (Ishikawa Prefectural Central Hospital), Masako Kadowaki (NTT Medical Center Tokyo), Takahiro Ito (Chiba Hospital), Mika Ishimaru (Ehime Prefectural Central Hospital), and Kunihisa Tsukada (AIDS Clinical Center).
We all declare no conflicts of interest. All the authors have submitted the ICMJE form for the disclosure of potential conflicts of interest. Any conflict that the editors consider relevant to this article is disclosed here.
H.H. and Y.T. designed the study protocol. A.T., H.H., Y.T., and T.Y. recruited participating hospitals. T.Y. and A.W. provided microbiological data on isolated Nocardia species. The on-site investigators collected clinical data. A.T. and H.H. performed the data analysis. A.T. drafted the first version of the manuscript. A.T. and H.H. revised the manuscript. All the authors critically reviewed and contributed to the final version of manuscript.
Footnotes
Supplemental material is available online only.
Contributor Information
Hitoshi Honda, Email: hhhhonda@gmail.com.
the Japan Nocardia Study Group:
Yasuo Takiguchi, Tamon Yagi, Masaru Amishima, Noritaka Sekiya, Meiwa Shibata, Ryota Hase, Yoshihiro Kobashi, Akira Nakamura, Katsushi Tajima, Nobuaki Mori, Takashi Ishiguro, Takeaki Sugawara, Hiroki Tateno, Nobuhiro Kodama, Masaru Ando, Hironori Uruga, Yoshifumi Uwamino, Yukimasa Ooi, Hanako Kurai, Takuya Washino, Akihiro Toguchi, Toshimasa Hayashi, Akihiro Sato, Yukari Shimizu, Hirokazu Toyoshima, Takeshi Kinjo, Kazuhiro Asada, Toshimi Oda, Kazuhito Saito, Kei Nakamura, Kenji Kubo, Yoichi Tagami, Yuji Miyoshi, Kenji Inoue, Takeaki Nishibori, Ken Tsutsumi, Tomokazu Kuchibiro, Yuka Ono, Akihiko Suganuma, Kentaro Okuda, Toshiki Furukawa, Masahiro Kobayashi, Yohei Kanzawa, Haruka Ando, Yuriko Ichikawa, Nobumasa Okumura, Takehito Kobayashi, Yoichi Ohtake, Naofumi Chinen, Hiroshi Morioka, Miwa Iio, Akihiro Ueda, Takeshi Nakazawa, Takahiro Matsuo, Hideki Koketsu, Tatsuya Saito, Kenji Sakamoto, Nobujiro Abe, Takahiro Hosokawa, Ikkou Higashimoto, Fumihiro Ochi, Naofumi Kameyama, Shinya Tomari, Mari Yamamoto, Yasushi Shibue, Kazuya Iwai, Ryota Kominami, Satoshi Kimura, Shinji Iyama, Mika Shiotsuka, Masamitsu Ishihara, Nanako Tsutsui, Hirokazu Tojima, Hiroyuki Kouzai, Tatsuo Kato, Akira Iwashima, Akiko Ando, Kenya Sumitomo, Takafumi Okada, Takehito Fusegawa, Toshiyuki Harada, Kazuhiro Usui, Tamayo Watanabe, Masako Kadowaki, Takahiro Ito, Mika Ishimaru, and Kunihisa Tsukada
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