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Disseminated nocardiosis with Nocardia brasiliensis bacteremia in a patient with rheumatoid arthritis using tocilizumab
J Infect Chemother 25 (2019) 552e555
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case Report
Disseminated nocardiosis with Nocardia brasiliensis bacteremia in a patient with rheumatoid arthritis using tocilizumab* Ryosuke Yamate a, Takashi Matono a, *, Takashi Yaguchi d, Yusuke Fujii b, Yuki Goto c, Kazunori Tobino c, Hiroshi Imura a, Shuji Nagano b a
Department of General Internal Medicine, Iizuka, Japan Department of Rheumatology, Iizuka, Japan Respiratory Medicine, Iizuka Hospital, Iizuka, Japan d Medical Mycology Research Center, Chiba University, Chiba, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 September 2018 Received in revised form 8 January 2019 Accepted 13 February 2019 Available online 7 March 2019
Here, we present a case of disseminated nocardiosis, involving pneumonia, percutaneous abscess, and bacteremia, in a 67-year-old Japanese woman. She had also been treated for rheumatoid arthritis with prednisolone, methotrexate, and tocilizumab (interleukin-6 receptor inhibitor). Based on the 16S rRNA sequence analysis and a blast search, we identified the isolate as Nocardia brasiliensis. We discontinued methotrexate and tocilizumab on admission, and administered intravenous antimicrobial combination therapy for 6 weeks, followed by oral trimethoprim-sulfamethoxazole for 12 months, in total. Nocardia bacteremia is rare, often difficult to diagnose, and substantially fatal. However, due to our prompt diagnosis within one day of the onset of symptoms, and administration of appropriate treatment based on antimicrobial susceptibilities, this patient succeeded in surviving the infection. Not only microbiologists but also clinicians should be aware of the characteristic bacterial form of Gram/Kinyoun staining for early recognition of nocardiosis. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Disseminated nocardiosis Nocardia bacteremia Rheumatoid arthritis Tocilizumab
1. Introduction Nocardia is a gram-positive aerobic actinomycete found in the soil and waterside [1]. Nocardiosis is known to be an opportunistic infection, with approximately 60% of cases occurring in immunocompromised patients, such as those with HIV infections, hematologic malignancies, or those who have had organ transplantation, and/or steroid-treatment [2,3]. Among more than 80 known Nocardia species (spp), at least 49 have been considered to be clinically pathogenic to humans [1,4,5]. The antimicrobial susceptibilities of the isolates vary depending on the species. Therefore, performing an antimicrobial susceptibility test is essential before deciding on the treatment. Nocardia bacteremia is rare and occurs in approximately 1.3e7.7% of patients with Nocardia infection [6,7]. Additionally, disseminated nocardiosis has been reported in
*
All authors meet the ICMJE authorship criteria. * Corresponding author. Department of General Internal Medicine, Iizuka Hospital, 3-83 Yoshino-machi, Iizuka, Fukuoka, 820-8505, Japan. E-mail address: [email protected] (T. Matono).
patients with traumatic wounds, animal bites, a central venous catheter, and in those who are immunocompromised [2,17]. The mortality rate of patients with Nocardia bacteremia is potentially high and has been reported to be approximately 50% [8]. Here, we present the case of a patient with rheumatoid arthritis and drugmediated immunosuppression, who survived a disseminated N. brasiliensis infection with pneumonia, subcutaneous abscess, and bacteremia.
2. Case report A 67-year-old Japanese woman with rheumatoid arthritis presented with two days of general malaise without high fever and chill. She had been taking prednisolone (7.5 mg per day) and methotrexate (8 mg per week) for a decade, and tocilizumab (inhibitor of interleukin-6 [IL-6] receptor; 162 mg per 2 weeks) for 2 months for rheumatoid arthritis. Physical examination at the time of admission showed the following: Glasgow Coma Scale: 14 (confused), body temperature: 37.4 C (97.2 F), blood pressure: 86/ 61 mmHg, heart rate: 122 beats per minute, respiratory rate: 24
https://doi.org/10.1016/j.jiac.2019.02.005 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
R. Yamate et al. / J Infect Chemother 25 (2019) 552e555
breaths per minute, oxygen saturation: 100% under 8 L/minute of oxygen, and attenuation of bilateral breath sounds with coarse crackles in the right lower lung field. Laboratory findings revealed the presence of elevated neutrophil-dominant white blood cells: neutrophils: 7280/mL (94.4%), C-reactive protein: 35.2 mg/L, and serum immunoglobulin M (IgM): 25 mg/dl, IgG: 791 mg/dl, and IgA: 33 mg/dl. Chest computed tomography (CT) showed multiple nodules in both lungs and some consolidations with decreased enhancement areas suggesting diffusely distributed multiple abscesses in the right middle and lower lung lobe with pleural effusion (Fig. 1). We also found subcutaneous abscesses in the right buttock by ultrasound and CT. We attempted to collect abscess specimen by puncturing it but could not obtain it. Following an initial diagnosis of sepsis (quick SOFA score: 3) [9], we administered intravenous meropenem and vancomycin and discontinued methotrexate and tocilizumab. On the day of admission, Gram staining detected Actinomycetes-like Gram-positive bacilli in the sputum specimen, and Kinyoun staining, thereafter, indicated the possibility of Nocardia sp. infection (Fig. 2). We started the patient on meropenem and trimethoprim-sulfamethoxazole as induction therapy for pulmonary nocardiosis. Since the Nocardia sp. takes 5 days to grow in blood culture (Fig. 3), we also initiated treatment with amikacin following a diagnosis of severe disseminated nocardiosis. Based on the 16S rRNA nucleotide sequence and results of a blast search carried out at the Medical Mycology Research Center, Chiba University, the isolates were identified as N. brasiliensis, which showed 99.9% (1473/1474 bp) similarity to the N. brasiliensis strain DSM43758T (Genbank Accession No.: AF430038). After ruling out a brain abscess by contrast-enhanced magnetic resonance imaging, we continued the intravenous meropenem and trimethoprim-sulfamethoxazole. Based on the susceptibilities of N. brasiliensis (Table 1) [10], we switched to oral trimethoprim-sulfamethoxazole as maintenance therapy after the 6-week intravenous combination therapy. We ruled out superinfections with bacteria, fungus, and mycobacterium based on findings from cultures, PCR tests for tuberculosis and Mycobacterium avium complex organisms, and pathologies of blood, sputum, bronchoalveolar lavage fluid and lung biopsy specimens. Tests for the Cryptococcus antigen, galactomannan antigen, and interferon-gamma release assay (T-SPOT) were also negative. The CT images and ultrasound after the intravenous combination therapy showed improvement in the lung nodules and consolidations as well as in the subcutaneous abscess in the right buttock. The patient finally recovered after 12 months of treatment with oral trimethoprim-sulfamethoxazole without any events of immune reconstitution after stopping tocilizumab.
553
Fig. 2. Kinyoun staining of sputum specimen ( 1000). The branching filamentous bacilli show acid-fastness with Kinyoun staining under microscopic examination.
Fig. 3. Gram staining of blood culture specimen ( 1000). Microscopic examination shows the branching filamentous and polymorphic Gram-positive bacilli, identified as N. brasiliensis.
3. Discussion We report a case of disseminated Nocardia infection with pneumonia, bacteremia, and percutaneous abscess in a patient with rheumatoid arthritis using a biological product. Although the mortality rate for disseminated nocardiosis particularly with
bacteremia is substantially high, this patient was able to survive the infection. Here, we discuss the potential factors that we believe were responsible for the complete recovery of this patient. First, the diagnosis of nocardiosis is often challenging because it is difficult to recover sufficient Nocardia spp. from inadequate
Fig. 1. Pulmonary nocardiosis at the time of admission. Computed tomography image shows multiple nodules in both lungs and some consolidations with decreased enhancement areas suggesting diffusely distributed multiple abscesses.
554
R. Yamate et al. / J Infect Chemother 25 (2019) 552e555
Table 1 Susceptibility of Nocardia brasiliensis isolate to different antimicrobials. Antimicrobials
MIC
Susceptibilitya
Trimethoprim-Sulfamethoxazole Amikacin Gentamicin Tobramycin Imipenem Linezolid Ciprofloxacin Ceftriaxone Cefotaxim Cefepim Doxycycline Minocycline Clarithromycin
19/1 1 <0.5 <0.5 2 4 >4 >64 >64 >32 2 1 >8
S S S S S S R R R R I S R
MIC, minimum inhibitory concentration; S, susceptible; I, intermediate; R, resistant. a Susceptibility of the isolate to antimicrobials was defined according to the CLSI M24-A guidelines.
specimens in order to obtain a detectable yield in the laboratory. The culture detection rates from sputum specimens obtained by noninvasive procedures are reported to be less than 44% [11]. Moreover, Nocardia spp. generally, require a long growth period of 5e21 days by routine culture methods [12]. Several reports have emphasized that early diagnosis is an important factor for good prognosis [13e15]. Two studies describing 11/31 (31%) [15], and 50/ 117 (43%) [7] cases of disseminated nocardiosis found that the median time from the onset of symptoms to diagnosis was 30 and 20 days, respectively, and the mortality rates were 39% [15] and 16% [7], respectively. Contrary to these reports, based on Gram/Kinyoun staining and chest image findings, we were able to promptly diagnose nocardiosis and administer the proper antimicrobials within a day of the onset of symptoms, which we believe was an important factor for the good clinical outcome. The image findings in patients with pulmonary nocardiosis are varied [2]. These include nodules and cavitation (>75%) which are the most common, followed by pleural effusion, consolidation and ground-glass opacity (50%) [16], which were seen in this case as well. Second, a combination of antimicrobials is typically given as induction therapy in cases of severe nocardiosis because the antimicrobial susceptibilities are diverse and depend on the involved species [17]. We, therefore, evaluated the general characteristics of the species-specific antimicrobial susceptibilities in the Nocardia isolates. While N. abscessus, N. paucivorans, N. otitidiscaviarum, and N. brasiliensis commonly tend to be resistant to imipenem, N. farcinica and N. otitidiscaviarum are resistant to trimethoprimsulfamethoxazole [17]. N. brasiliensis, which was detected in this case, has been reported to have resistance rates (to imipenem) of 60e80% [6]. However, in our patient, N. brasiliensis was susceptible to imipenem, which may be another factor that led to her recovery. In addition, because the isolates were susceptible to trimethoprimsulfamethoxazole, we could also give her oral trimethoprimsulfamethoxazole as maintenance therapy. Therefore, determination of antimicrobial susceptibilities of the Nocardia spp. is extremely important for treatment decisions and should be performed on all isolates. Third, we investigated the patient's medical history for other diseases and the use of immunosuppressive drugs. In general, Nocardia infections occur in immunocompromised patients. According to a review on Nocardia infections from 1950 to 2000, 61% of these infections occurred in immunocompromised patients including those with organ transplantations, hematologic malignancies, solid tumors, and HIV infections [2]. Furthermore, biological products used for the treatment of rheumatoid arthritis have been shown to increase the incidence of nocardiosis,
granulomatous diseases, cytomegalovirus infections, and fungal infections [18]. One such biological product, infliximab, an antitumor necrosis factor-a inhibitor, has been found to be commonly used among patients with Nocardia infection [19,20]. Tocilizumab, an inhibitor of the IL-6 receptor, has been shown to frequently induce serious infections in patients with rheumatoid arthritis who are being treated with methotrexate and/or prednisolone (up to 10 mg/day) [21]. However, there is little information on the causal relationship between the inhibitors of IL-6 receptor and nocardiosis. Although our patient had no serious underlying diseases causing her to be immunocompromised, the use of immunosuppressive drugs including prednisolone, methotrexate, and tocilizumab could have contributed to the development of disseminated nocardiosis. We believe that discontinuing the immunosuppressive therapy may have played an important role in improving her immunity, allowing her to recover from the disseminated nocardiosis, which is in line with a previous report [22]. Finally, severe nocardiosis occasionally is accompanied by superinfections such as fungal, mycobacterial, and viral infections. Among cases of pulmonary nocardiosis, 23.3% had co-infections with Aspergillus spp., cytomegalovirus, or Pneumocystis jiroveci [23]. Furthermore, affinity to the central nervous system (CNS) differs among the species. CNS involvement was observed in 80e35% of N. asteroides and 19% of N. farcinica but only in 5e3.5% of N. brasiliensis [2,24]. Additionally, trimethoprim-sulfamethoxazole often induces several adverse reactions such as renal disorders, myelosuppression, and electrolyte abnormalities [25]. The absence of superinfections, CNS infections, and adverse reactions to the antimicrobials also would have contributed to the good clinical outcome in this case. We have reported an interesting case of disseminated nocardiosis with bacteremia, wherein a prompt diagnosis, cutting back on the ongoing immunosuppressive therapy, and administration of appropriate antimicrobial agents all contributed to a positive clinical outcome and helped the patient in surviving the infection.
Funding There is no funding source.
Conflicts of interest All authors declare no conflicts of interest.
Ethics approval and patient's consent A statement of the ethics committee was not required for this anonymized case report, in accordance with the legislation of the Institutional Review Committee of Iizuka Hospital. Verbal consent for publication was obtained from the individual patient described in this report and was documented in the medical chart.
Acknowledgments The authors thank the physicians, nurses, and clinical staffs at the Iizuka Hospital for their excellent work. We also acknowledge the staff of the Medical Mycology Research Center, Chiba University for performing the microbiological analyses. We also thank Yoshimi Furuno, Yuji Teshima, and the microbiologists at the Iizuka Hospital for their help with the microbiological analyses.
R. Yamate et al. / J Infect Chemother 25 (2019) 552e555
References [1] Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev 2006;19:259e82. [2] Beaman BL, Beaman L. Nocardia species: host-parasite relationships. Clin Microbiol Rev 1994;7:213e64. n PM, Bouza E, Mun ~ oz P. Nocar[3] Minero MV, Marín M, Cercenado E, Rabada diosis at the turn of the century. Medicine (Baltim) 2009;88:250e61. [4] Jorgensen JH, Pfaller MA, Carroll KC, American Society of Microbiology. Manual of clinical microbiology. 11th ed. Washington, DC: ASM Press; 2015. [5] Roth A, Andrees S, Kroppenstedt RM, Harmsen D, Mauch H. Phylogeny of the genus Nocardia based on reassessed 16S rRNA gene sequences reveals underspeciation and division of strains classified as Nocardia asteroides into three established species and two unnamed taxons. J Clin Microbiol 2003;41: 851e6. n P, Navarro AM, [6] Valdezate S, Garrido N, Carrasco G, Medina-Pascual MJ, Villalo et al. Epidemiology and susceptibility to antimicrobial agents of the main Nocardia species in Spain. J Antimicrob Chemother 2017;72:754e61. [7] Coussement J, Lebeaux D, van Delden C, Guillot H, Freund R, Marbus S, et al. Nocardia infection in solid organ transplant recipients: a multicenter european case-control study. Clin Infect Dis 2016;63:338e45. [8] Kontoyiannis DP, Ruoff K, Hooper DC. Nocardia bacteremia. Report of 4 cases and review of the literature. Medicine (Baltim) 1998;77:255e67. [9] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). J Am Med Assoc 2016;315(8):801e10. [10] Clinical and Laboratory Standards Institute. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes. Approved standard. CLSI Document M24-A. Wayne, PA: CLSI; 2003. [11] Georghiou PR, Blacklock ZM. Infection with Nocardia species in Queensland. A review of 102 clinical isolates. Med J Aust 1992;156:692e7. [12] Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltim) 2004;83:300e13.
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[13] Matulionyte R, Rohner P, Uçkay I, Lew D, Garbino J. Secular trends of nocardia infection over 15 years in a tertiary care hospital. J Clin Pathol 2004;57:807e12. [14] Palmer DL, Harvey RL, Wheeler JK. Diagnostic and therapeutic considerations in Nocardia asteroides infection. Medicine (Baltim) 1974;53:391e401. s R, Mene ndez Villanueva R, Reyes Calzada S, Santos [15] Martínez Toma s Tarazona JM, Modesto Alapont M, et al. Pulmonary Durantez M, Valle nocardiosis: risk factors and outcomes. Respirology 2007;12:394e400. [16] Chen J, Zhou H, Xu P, Zhang P, Ma S, Zhou J. Clinical and radiographic characteristics of pulmonary nocardiosis: clues to earlier diagnosis. PLoS One 2014;9(3):e90724. [17] Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc 2012;87:403e7. [18] Salvana EM, Salata RA. Infectious complications associated with monoclonal antibodies and related small molecules. Clin Microbiol Rev 2009;22:274e90. [19] Garner O, Ramirez-Berlioz A, Iardino A, Mocherla S, Bhairavarasu K. Disseminated nocardiosis associated with treatment with infliximab in a patient with ulcerative colitis. Am J Case Rep 2017;18:1365e9. [20] Abreu C, Rocha-Pereira N, Sarmento A, Magro F. Nocardia infections among immunomodulated inflammatory bowel disease patients: a review. World J Gastroenterol 2015;21:6491e8. [21] Baek HJ, Lim MJ, Park W, Park SH, Shim SC, Yoo DH, et al. Efficacy and safety of tocilizumab in Korean patients with active rheumatoid arthritis. Korean J Intern Med 2018 Jan 17. https://doi.org/10.3904/kjim.2017.159. PMID: 29334721. [22] van Dijk K, van Kessel DA, Schijffelen MJ, Staartjes WR, Tersmette M. Disseminated Nocardia infection: spontaneous resolution in response to decrease of immunosuppression. New Microbes New Infect 2015;3:10e1. [23] Takiguchi Y, Ishizaki S, Kobayashi T, Sato S, Hashimoto Y, Suruga Y, et al. Pulmonary nocardiosis: a clinical analysis of 30 cases. Intern Med 2017;56:1485e90. [24] Anagnostou T, Arvanitis M, Kourkoumpetis TK, Desalermos A, Carneiro HA, Mylonakis E. Nocardiosis of the central nervous system: experience from a general hospital and review of 84 cases from the literature. Medicine (Baltim) 2014;93(1):19e32. [25] Ho JM, Juurlink DN. Considerations when prescribing trimethoprim- sulfamethoxazole. CMAJ (Can Med Assoc J) 2011;183:1851e8.
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case Report
Disseminated nocardiosis with Nocardia brasiliensis bacteremia in a patient with rheumatoid arthritis using tocilizumab* Ryosuke Yamate a, Takashi Matono a, *, Takashi Yaguchi d, Yusuke Fujii b, Yuki Goto c, Kazunori Tobino c, Hiroshi Imura a, Shuji Nagano b a
Department of General Internal Medicine, Iizuka, Japan Department of Rheumatology, Iizuka, Japan Respiratory Medicine, Iizuka Hospital, Iizuka, Japan d Medical Mycology Research Center, Chiba University, Chiba, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 September 2018 Received in revised form 8 January 2019 Accepted 13 February 2019 Available online 7 March 2019
Here, we present a case of disseminated nocardiosis, involving pneumonia, percutaneous abscess, and bacteremia, in a 67-year-old Japanese woman. She had also been treated for rheumatoid arthritis with prednisolone, methotrexate, and tocilizumab (interleukin-6 receptor inhibitor). Based on the 16S rRNA sequence analysis and a blast search, we identified the isolate as Nocardia brasiliensis. We discontinued methotrexate and tocilizumab on admission, and administered intravenous antimicrobial combination therapy for 6 weeks, followed by oral trimethoprim-sulfamethoxazole for 12 months, in total. Nocardia bacteremia is rare, often difficult to diagnose, and substantially fatal. However, due to our prompt diagnosis within one day of the onset of symptoms, and administration of appropriate treatment based on antimicrobial susceptibilities, this patient succeeded in surviving the infection. Not only microbiologists but also clinicians should be aware of the characteristic bacterial form of Gram/Kinyoun staining for early recognition of nocardiosis. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Disseminated nocardiosis Nocardia bacteremia Rheumatoid arthritis Tocilizumab
1. Introduction Nocardia is a gram-positive aerobic actinomycete found in the soil and waterside [1]. Nocardiosis is known to be an opportunistic infection, with approximately 60% of cases occurring in immunocompromised patients, such as those with HIV infections, hematologic malignancies, or those who have had organ transplantation, and/or steroid-treatment [2,3]. Among more than 80 known Nocardia species (spp), at least 49 have been considered to be clinically pathogenic to humans [1,4,5]. The antimicrobial susceptibilities of the isolates vary depending on the species. Therefore, performing an antimicrobial susceptibility test is essential before deciding on the treatment. Nocardia bacteremia is rare and occurs in approximately 1.3e7.7% of patients with Nocardia infection [6,7]. Additionally, disseminated nocardiosis has been reported in
*
All authors meet the ICMJE authorship criteria. * Corresponding author. Department of General Internal Medicine, Iizuka Hospital, 3-83 Yoshino-machi, Iizuka, Fukuoka, 820-8505, Japan. E-mail address: [email protected] (T. Matono).
patients with traumatic wounds, animal bites, a central venous catheter, and in those who are immunocompromised [2,17]. The mortality rate of patients with Nocardia bacteremia is potentially high and has been reported to be approximately 50% [8]. Here, we present the case of a patient with rheumatoid arthritis and drugmediated immunosuppression, who survived a disseminated N. brasiliensis infection with pneumonia, subcutaneous abscess, and bacteremia.
2. Case report A 67-year-old Japanese woman with rheumatoid arthritis presented with two days of general malaise without high fever and chill. She had been taking prednisolone (7.5 mg per day) and methotrexate (8 mg per week) for a decade, and tocilizumab (inhibitor of interleukin-6 [IL-6] receptor; 162 mg per 2 weeks) for 2 months for rheumatoid arthritis. Physical examination at the time of admission showed the following: Glasgow Coma Scale: 14 (confused), body temperature: 37.4 C (97.2 F), blood pressure: 86/ 61 mmHg, heart rate: 122 beats per minute, respiratory rate: 24
https://doi.org/10.1016/j.jiac.2019.02.005 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
R. Yamate et al. / J Infect Chemother 25 (2019) 552e555
breaths per minute, oxygen saturation: 100% under 8 L/minute of oxygen, and attenuation of bilateral breath sounds with coarse crackles in the right lower lung field. Laboratory findings revealed the presence of elevated neutrophil-dominant white blood cells: neutrophils: 7280/mL (94.4%), C-reactive protein: 35.2 mg/L, and serum immunoglobulin M (IgM): 25 mg/dl, IgG: 791 mg/dl, and IgA: 33 mg/dl. Chest computed tomography (CT) showed multiple nodules in both lungs and some consolidations with decreased enhancement areas suggesting diffusely distributed multiple abscesses in the right middle and lower lung lobe with pleural effusion (Fig. 1). We also found subcutaneous abscesses in the right buttock by ultrasound and CT. We attempted to collect abscess specimen by puncturing it but could not obtain it. Following an initial diagnosis of sepsis (quick SOFA score: 3) [9], we administered intravenous meropenem and vancomycin and discontinued methotrexate and tocilizumab. On the day of admission, Gram staining detected Actinomycetes-like Gram-positive bacilli in the sputum specimen, and Kinyoun staining, thereafter, indicated the possibility of Nocardia sp. infection (Fig. 2). We started the patient on meropenem and trimethoprim-sulfamethoxazole as induction therapy for pulmonary nocardiosis. Since the Nocardia sp. takes 5 days to grow in blood culture (Fig. 3), we also initiated treatment with amikacin following a diagnosis of severe disseminated nocardiosis. Based on the 16S rRNA nucleotide sequence and results of a blast search carried out at the Medical Mycology Research Center, Chiba University, the isolates were identified as N. brasiliensis, which showed 99.9% (1473/1474 bp) similarity to the N. brasiliensis strain DSM43758T (Genbank Accession No.: AF430038). After ruling out a brain abscess by contrast-enhanced magnetic resonance imaging, we continued the intravenous meropenem and trimethoprim-sulfamethoxazole. Based on the susceptibilities of N. brasiliensis (Table 1) [10], we switched to oral trimethoprim-sulfamethoxazole as maintenance therapy after the 6-week intravenous combination therapy. We ruled out superinfections with bacteria, fungus, and mycobacterium based on findings from cultures, PCR tests for tuberculosis and Mycobacterium avium complex organisms, and pathologies of blood, sputum, bronchoalveolar lavage fluid and lung biopsy specimens. Tests for the Cryptococcus antigen, galactomannan antigen, and interferon-gamma release assay (T-SPOT) were also negative. The CT images and ultrasound after the intravenous combination therapy showed improvement in the lung nodules and consolidations as well as in the subcutaneous abscess in the right buttock. The patient finally recovered after 12 months of treatment with oral trimethoprim-sulfamethoxazole without any events of immune reconstitution after stopping tocilizumab.
553
Fig. 2. Kinyoun staining of sputum specimen ( 1000). The branching filamentous bacilli show acid-fastness with Kinyoun staining under microscopic examination.
Fig. 3. Gram staining of blood culture specimen ( 1000). Microscopic examination shows the branching filamentous and polymorphic Gram-positive bacilli, identified as N. brasiliensis.
3. Discussion We report a case of disseminated Nocardia infection with pneumonia, bacteremia, and percutaneous abscess in a patient with rheumatoid arthritis using a biological product. Although the mortality rate for disseminated nocardiosis particularly with
bacteremia is substantially high, this patient was able to survive the infection. Here, we discuss the potential factors that we believe were responsible for the complete recovery of this patient. First, the diagnosis of nocardiosis is often challenging because it is difficult to recover sufficient Nocardia spp. from inadequate
Fig. 1. Pulmonary nocardiosis at the time of admission. Computed tomography image shows multiple nodules in both lungs and some consolidations with decreased enhancement areas suggesting diffusely distributed multiple abscesses.
554
R. Yamate et al. / J Infect Chemother 25 (2019) 552e555
Table 1 Susceptibility of Nocardia brasiliensis isolate to different antimicrobials. Antimicrobials
MIC
Susceptibilitya
Trimethoprim-Sulfamethoxazole Amikacin Gentamicin Tobramycin Imipenem Linezolid Ciprofloxacin Ceftriaxone Cefotaxim Cefepim Doxycycline Minocycline Clarithromycin
19/1 1 <0.5 <0.5 2 4 >4 >64 >64 >32 2 1 >8
S S S S S S R R R R I S R
MIC, minimum inhibitory concentration; S, susceptible; I, intermediate; R, resistant. a Susceptibility of the isolate to antimicrobials was defined according to the CLSI M24-A guidelines.
specimens in order to obtain a detectable yield in the laboratory. The culture detection rates from sputum specimens obtained by noninvasive procedures are reported to be less than 44% [11]. Moreover, Nocardia spp. generally, require a long growth period of 5e21 days by routine culture methods [12]. Several reports have emphasized that early diagnosis is an important factor for good prognosis [13e15]. Two studies describing 11/31 (31%) [15], and 50/ 117 (43%) [7] cases of disseminated nocardiosis found that the median time from the onset of symptoms to diagnosis was 30 and 20 days, respectively, and the mortality rates were 39% [15] and 16% [7], respectively. Contrary to these reports, based on Gram/Kinyoun staining and chest image findings, we were able to promptly diagnose nocardiosis and administer the proper antimicrobials within a day of the onset of symptoms, which we believe was an important factor for the good clinical outcome. The image findings in patients with pulmonary nocardiosis are varied [2]. These include nodules and cavitation (>75%) which are the most common, followed by pleural effusion, consolidation and ground-glass opacity (50%) [16], which were seen in this case as well. Second, a combination of antimicrobials is typically given as induction therapy in cases of severe nocardiosis because the antimicrobial susceptibilities are diverse and depend on the involved species [17]. We, therefore, evaluated the general characteristics of the species-specific antimicrobial susceptibilities in the Nocardia isolates. While N. abscessus, N. paucivorans, N. otitidiscaviarum, and N. brasiliensis commonly tend to be resistant to imipenem, N. farcinica and N. otitidiscaviarum are resistant to trimethoprimsulfamethoxazole [17]. N. brasiliensis, which was detected in this case, has been reported to have resistance rates (to imipenem) of 60e80% [6]. However, in our patient, N. brasiliensis was susceptible to imipenem, which may be another factor that led to her recovery. In addition, because the isolates were susceptible to trimethoprimsulfamethoxazole, we could also give her oral trimethoprimsulfamethoxazole as maintenance therapy. Therefore, determination of antimicrobial susceptibilities of the Nocardia spp. is extremely important for treatment decisions and should be performed on all isolates. Third, we investigated the patient's medical history for other diseases and the use of immunosuppressive drugs. In general, Nocardia infections occur in immunocompromised patients. According to a review on Nocardia infections from 1950 to 2000, 61% of these infections occurred in immunocompromised patients including those with organ transplantations, hematologic malignancies, solid tumors, and HIV infections [2]. Furthermore, biological products used for the treatment of rheumatoid arthritis have been shown to increase the incidence of nocardiosis,
granulomatous diseases, cytomegalovirus infections, and fungal infections [18]. One such biological product, infliximab, an antitumor necrosis factor-a inhibitor, has been found to be commonly used among patients with Nocardia infection [19,20]. Tocilizumab, an inhibitor of the IL-6 receptor, has been shown to frequently induce serious infections in patients with rheumatoid arthritis who are being treated with methotrexate and/or prednisolone (up to 10 mg/day) [21]. However, there is little information on the causal relationship between the inhibitors of IL-6 receptor and nocardiosis. Although our patient had no serious underlying diseases causing her to be immunocompromised, the use of immunosuppressive drugs including prednisolone, methotrexate, and tocilizumab could have contributed to the development of disseminated nocardiosis. We believe that discontinuing the immunosuppressive therapy may have played an important role in improving her immunity, allowing her to recover from the disseminated nocardiosis, which is in line with a previous report [22]. Finally, severe nocardiosis occasionally is accompanied by superinfections such as fungal, mycobacterial, and viral infections. Among cases of pulmonary nocardiosis, 23.3% had co-infections with Aspergillus spp., cytomegalovirus, or Pneumocystis jiroveci [23]. Furthermore, affinity to the central nervous system (CNS) differs among the species. CNS involvement was observed in 80e35% of N. asteroides and 19% of N. farcinica but only in 5e3.5% of N. brasiliensis [2,24]. Additionally, trimethoprim-sulfamethoxazole often induces several adverse reactions such as renal disorders, myelosuppression, and electrolyte abnormalities [25]. The absence of superinfections, CNS infections, and adverse reactions to the antimicrobials also would have contributed to the good clinical outcome in this case. We have reported an interesting case of disseminated nocardiosis with bacteremia, wherein a prompt diagnosis, cutting back on the ongoing immunosuppressive therapy, and administration of appropriate antimicrobial agents all contributed to a positive clinical outcome and helped the patient in surviving the infection.
Funding There is no funding source.
Conflicts of interest All authors declare no conflicts of interest.
Ethics approval and patient's consent A statement of the ethics committee was not required for this anonymized case report, in accordance with the legislation of the Institutional Review Committee of Iizuka Hospital. Verbal consent for publication was obtained from the individual patient described in this report and was documented in the medical chart.
Acknowledgments The authors thank the physicians, nurses, and clinical staffs at the Iizuka Hospital for their excellent work. We also acknowledge the staff of the Medical Mycology Research Center, Chiba University for performing the microbiological analyses. We also thank Yoshimi Furuno, Yuji Teshima, and the microbiologists at the Iizuka Hospital for their help with the microbiological analyses.
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