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93 Streptomyces Pneumonia in a Patient with Human Immunodeficiency Virus Infection: Case Report and Review of the Literature on Invasive Streptomyces Infections Eileen F. Dunne, William J. Burman, and Michael L. Wilson From the Department of Public Health, Denver Health and Hospitals; and the Departments of Medicine (Division of Infectious Diseases) and Pathology, University of Colorado Health Sciences Center, Denver, Colorado Streptomyces species are most widely known for their production of antimicrobial substances and, apart from mycetoma, have rarely been reported as a cause of infection. We describe a patient with early human immunodeficiency virus infection who presented with fever, cough, and nodular pulmonary infiltrates. Open lung biopsy revealed necrotic tissue and a sulfur granule; aerobic bacterial cultures yielded Streptomyces species. The patient was treated successfully with clarithromycin for 6 months. We review the clinical presentation and treatment of invasive streptomyces infections. Members of the genus Streptomyces are aerobic actinomycetes known for the production of antibiotics used to treat bacterial, mycobacterial, fungal, and parasitic infections. Streptomyces species can also cause human disease. Mycetoma, a chronic suppurative infection of the skin and underlying soft tissue, is the most common presentation of streptomyces infection; visceral infections with these organisms appear to be rare. We report a case of pneumonia caused by Streptomyces species in a patient with HIV infection, and we review the literature on invasive streptomyces infections. Case Report A 43-year-old male presented with complaints of progressive weight loss over 2 months, night sweats and fatigue of 2 weeks’ duration, a nonproductive cough, dyspnea, and pleuritic chest pain. HIV infection had been diagnosed 8 years previously; his most recent CD4 cell count was 800/mm3. Notable findings of the initial physical examination included a temperature of 38.97C, diffuse inspiratory crackles, and a right-sided pleural friction rub. The patient had no evidence of dental abnormalities. Laboratory tests revealed a WBC count of 15,800 cells/mm3 and modest increases in levels of alkaline phosphatase, lactate dehydrogenase, and hepatic transaminases. A chest radiograph (figure 1A) showed multiple, 0.5 – 3.0-cm, nodular opacities in both lung fields; a CT scan of the chest did not show any cavitation within these lesions or any intrathoracic lymphadenopathy (figure 1B). An initial sputum culture yielded normal oral flora. Received 16 September 1997; revised 11 February 1998. Reprints or correspondence: Dr. William J. Burman, Denver Public Health, 605 Bannock Street, Denver Colorado 80204. Clinical Infectious Diseases 1998;27:93–6 q 1998 by the Infectious Diseases Society of America. All rights reserved. 1058–4838/98/2701–0019$03.00 / 9c51$$jy13 06-15-98 22:53:06 Therapy with ceftriaxone and prophylactic doses of trimethoprim-sulfamethoxazole (TMP-SMZ) was started while awaiting further diagnostic studies. An open lung biopsy revealed acute and organizing pneumonia with focal necrosis and a sulfur granule (figure 2). Within the sulfur granule there was evidence of branching organisms with a beaded appearance on gram staining. Aerobic culture of the tissue biopsy specimen on blood agar yielded a beaded gram-positive bacterium that did not stain partially acid fast. All anaerobic, fungal, and mycobacterial cultures of the operative specimen were negative. This organism was identified as Streptomyces on the basis of morphology; negative partial acid-fast staining; sensitivity to lysozyme; and hydrolysis of xanthine, tyrosine, and casein [1]. The organism was confirmed to be a Streptomyces species at the Centers for Disease Control and Prevention (CDC) on the basis of cell-wall studies that demonstrated the presence of L-diaminopimelic acid [1, 2]. A susceptibility panel performed with use of the broth microdilution technique at the CDC showed that the isolate was susceptible to TMP-SMZ (MIC, õ0.06/1.19 mg/mL), imipenem (MIC Å 0.25 mg/mL), ceftriaxone (MIC, õ1.0 mg/mL), and clarithromycin (MIC, õ0.13 mg/mL) [3]. The patient’s condition improved clinically after treatment with ceftriaxone, which was switched to that with oral TMP-SMZ (double-strength t.i.d.). He subsequently developed fevers and a rash, necessitating discontinuation of TMP-SMZ. He was then treated with clarithromycin (500 mg b.i.d.) on the basis of the in vitro susceptibility data as well as intolerance of TMP-SMZ, and his symptoms abated within 1 month. The nodular infiltrates resolved after 3 months. Treatment with clarithromycin was discontinued after 6 months, and no signs of relapse have been observed in follow-up evaluations performed over 8 months. Discussion and Review of the Literature The aerobic actinomycetes, including Streptomyces and Nocardia species, are bacteria that belong in the order Actino- cida UC: CID 94 Dunne, Burman, and Wilson CID 1998;27 (July) Figure 1. A, Anteroposterior chest radiograph obtained on admission demonstrates multiple 0.5 – 3.0-cm nodules in both lungs of a patient with streptomyces pneumonia. B, CT of the chest below the carina showing these nodules without evidence of cavitation. mycetales. At one time these microorganisms were classified as fungi because they possess true aerial hyphae, but they are now recognized as bacteria. Most actinomycetes are grampositive, filamentous, partially acid-fast, branched bacteria. Species of the genus Streptomyces are characterized by formation of extensive, branched aerial hyphae with long chains of conidia and the cell-wall peptidoglycan L-diaminopimelic acid [1, 2]. The natural habitat of most Streptomyces species is the soil, where they are found on surfaces that support their mycelial growth [4]. More than 3,100 Streptomyces species have been described [5]. Initially, identification to the species level was based on subjectively chosen morphological features. Recently, morphological characteristics have given way to more objective classification methods such as rapid enzyme tests of fluorophores [5, 6]. Currently, the species taxonomy is chang- Figure 2. Hematoxylin-eosin-stained section from the open lung biopsy specimen showing necrosis, neutrophilic inflammation, and a sulfur granule in the center of the field (original magnification, 1400). / 9c51$$jy13 06-15-98 22:53:06 ing rapidly as new techniques allow more specific differentiation. The clinical significance of recovering this organism is often unclear because there have been many reports of isolation of Streptomyces species without definitive evidence of its pathogenic role. S. violaceoruber, S. coelicolor, and S. albus have been isolated from dental caries, blood, tonsils, skin, and sputum [4]. S. candidus has been isolated from the purulent exudate of a fractured patella, S. horton from pus, and S. willmorei from a liver abscess [4]. In addition, S. gedaensis has been recovered from sputum and abscesses [4]. However, none of these reports described the Streptomyces species as the principal pathogen. Therefore, the role of Streptomyces species in visceral infections has been controversial in the setting of mixed infections in which other probable primary pathogens have also been isolated. The present case was unusual, as only three other cases of streptomyces pneumonia have been described [7 – 9]. It clearly illustrates the potential of Streptomyces species to cause invasive infection. Streptomyces was determined to be the primary pathogen because the histopathological finding of a sulfur granule was compatible with the presence of this organism, other pathogens were excluded by culture, and Streptomyces species were isolated in pure culture of the tissue specimens. In addition, the response to therapy was dramatic, although the therapy was active against organisms other than Streptomyces species. Histopathologic examination of the lung biopsy specimen revealed a sulfur granule, a finding typical of visceral actinomyces infection and visceral botryomycosis caused by bacteria such as Staphylococcus aureus and species of Pseudomonas or Proteus. In contrast, Nocardia species have been reported to cause sulfur granules in mycetomas but not in visceral infections [10]. Thus, we may add Streptomyces species to the list of potential pathogens causing sulfur granules in visceral infection. cida UC: CID CID 1998;27 (July) Streptomyces Pneumonia To identify all reports of invasive disease due to Streptomyces species, we performed a MEDLINE search of the worldwide literature through January 1997 and reviewed the references from previous papers on Streptomyces. Mycetomas are the most common clinical presentation of streptomyces infection, and S. somaliensis has been identified as one of the principal etiologic agents of actinomycetoma in South America, Africa, India, Mexico, Malaysia, and the United States [11, 12]. The clinical presentation, microbiology, and treatment of mycetoma have been reviewed previously; thus, we did not include this manifestation of streptomyces infection in our review. We defined invasive disease as infection other than superficial skin infections or mycetoma. There have been only a few reports of Streptomyces species causing infection other than mycetoma (table 1). Streptomyces species have been described as the cause of septicemia and primary lung involvement [7]; Streptomyces was cultured in a case of chronic pericarditis in which extensive disease was observed in histopathologic specimens [13]; a brain abscess has been attributed to S. griseus [14]; an abdominal abscess 95 with peritonitis was caused by S. somaliensis [15]; and a case of endocarditis has been attributed to Streptomyces species [16]. In the majority of these cases, the outcome was good, with resolution of the infection. Treatment included many different antimicrobials, some with in vitro activity against Streptomyces species. Infections caused by aerobic actinomycetes in patients with HIV disease have been attributed predominantly to Nocardia and Rhodococcus species. There have been only three case reports of streptomyces infection in HIV-infected patients. A report by Caron and colleagues [8] described a man with advanced HIV infection and nodular infiltrates on a chest radiograph. Streptomyces species grew in culture of a bronchoscopic specimen [8]. Ahmed and colleagues [9] described a case of streptomyces pneumonia and monoarthritis in a patient with advanced HIV disease. A case of lymphadenitis was attributed to Streptomyces species in an HIV-infected patient; however, Mycobacterium tuberculosis also grew in culture [17]. It is of interest that rhodococcus and nocardia infections in HIV-positive patients can present as nodular infiltrates, similar to the Table 1. Summary of data from cases of invasive infection with Streptomyces species. Case no. Reference Etiologic organism Presentation Culture Underlying condition Treatment 1 [PR] Streptomyces species Pneumonia Lung biopsy specimen HIV infection* 2 [7] Streptomyces species Pneumonia, sepsis Blood None 3 [8] Streptomyces species Pneumonia Bronchoscopic specimen HIV infection† 4 [9] Streptomyces species Pneumonia, monoarthritis Bronchial washings, knee aspirate HIV infection‡ 5 [13] Pericarditis Oxacillin, drainage [14] Brain abscess Pericardial biopsy specimen Abscess None 6 Streptomyces species S. griseus None 7 8 [15] [16] S. somaliensis Streptomyces species Peritonitis Endocarditis Abscess Blood None Prosthetic aortic valve 9 [17] Streptomyces species Lymphadenitis Cervical lymph node HIV infectionx Penicillin, streptomycin, oxytetracycline, drainage Sulfadiazine Vancomycin, gentamicin; then amikacin, imipenem TMP-SMZ Duration of treatment (mo) Outcome 6 Pneumonia resolved 1 Pneumonia resolved 1 Pneumonia resolved TMP-SMZ, ceftriaxone; then clarithromycin Penicillin, sulfadiazine, streptomycin, aureomycin Cefuroxime, amikacin; then amoxicillin/ clavulanate Piperacillin/ tazobactam; then imipenem NOTE. NA Å data not available; TMP-SMZ Å trimethoprim-sulfamethoxazole. * CD4 cell count, ú400/mm3. † CD4 cell count, 100/mm3. ‡ CD4 cell count, 122/mm3. § Poor dentition noted, believed to be the route of infection. x CD4 cell count, 83/mm3. # Mycobacterium tuberculosis isolated from lymph node as well; patient also treated with isoniazid, rifampin, and nystatin. / 9c51$$jy13 06-15-98 22:53:06 cida UC: CID NA NA Resolution of pneumonia, arthritis, and fever in 4 – 5 d NA 3 Abscess resolved§ NA 6 NA NA NA Progressive wasting for 15 mo 96 Dunne, Burman, and Wilson findings in our case and the case reported by Caron and colleagues [8]. Invasive streptomyces infection may be more common than these isolated case reports suggest. Many Streptomyces species have been found in clinical isolates, most commonly S. griseus and S. somaliensis [5, 18, 19]. The reference laboratory of the CDC has summarized the characteristics of aerobic actinomycetes sent for species identification and susceptibility testing between October 1985 and February 1988. S. griseus represented 7.7% of the clinical isolates, following only Nocardia and Actinomadura species in frequency [18]. Unfortunately, because of the lack of clinical information regarding these isolates, it is not known whether S. griseus was a primary pathogen. However, the frequency of S. griseus in the latter study suggests that streptomyces infections are underreported. Because of the paucity of well-documented cases, treatment recommendations for streptomyces infections must be based on in vitro data [18, 19] and analogies from treatment of nocardia infections [20]. In the CDC evaluation of aerobic actinomycetes, a spectrum of antimicrobials were tested against S. griseus [18]. On the basis of in vitro MICs and expected serum concentrations, the most active drugs appeared to be minocycline, imipenem, erythromycin, and doxycycline, with ú80% of strains susceptible. The aminoglycoside tested in this study appeared to have very favorable MICs as well. We used a macrolide for therapy in our patient on the basis of this in vitro data as well as the susceptibilities obtained from the CDC. It is of interest that 29% of the S. griseus strains in the above study were resistant to TMP-SMZ. This finding may be important because TMP-SMZ is often considered the drug of choice for treatment of nocardiosis. In the event that pathology could be attributed to an actinomycete and the laboratory distinction between actinomycetes has not yet been made, TMP-SMZ may not be the best choice. Aminoglycosides, however, appear to have very effective MICs for actinomycetes and may be appropriate for first-line therapy. Because of these in vitro results and the limited clinical experience, the best treatment options for visceral streptomyces infection might be macrolides, minocycline, doxycycline, ceftriaxone, amikacin, or imipenem. In contrast to the treatment of nocardiosis, TMP-SMZ may not be optimal treatment for invasive infection with Streptomyces species [18]. Recommendations for duration of treatment of streptomyces infections can only be extrapolated from experience with the treatment of nocardiosis. Given the good results of therapy for nocardiosis [20], a 6 – 12-month course of antibiotics should be adequate for treatment of invasive streptomyces infection. Clearly, further experience with invasive streptomyces infection is nec- / 9c51$$jy13 06-15-98 22:53:06 CID 1998;27 (July) essary to delineate the course of infection, treatment, and outcome. References 1. Beaman BL, Saubolle MA, Wallace RJ. Nocardia, Rhodococcus, Streptomyces, Oerskovia, and other aerobic actinomycetes of medical importance. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH. Manual of clinical microbiology. 6th ed. Washington DC: ASM Press, 1995:379 – 99. 2. Berd D. Nocardia asteroides, a taxonomic study with clinical correlations. Am Rev Respir Dis 1973; 108:665 – 81. 3. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. M7-A4. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1997. 4. Kutzner HJ. The family Streptomycetaceae. In: Starr MP, Stolp H, Truper HG, Balows A, Schlegel HG, eds. The prokaryotes: a handbook on habitats, isolation and identification of bacteria. 2nd ed. Berlin: Springer Verlag KG, 1981:2028 – 90. 5. McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol Rev 1994; 7:357 – 417. 6. Goodfellow M, Ferguson EV, Sanglier JJ. Numerical classification and identification of Streptomyces species. Gene 1992; 115:225 – 33. 7. Kohn PM, Tager M, Siegel ML, Ashe R. Aerobic actinomyces septicemia: report of a case. N Engl J Med 1951; 245:640 – 4. 8. Caron F, Borsa-Lebas F, Boiron P, et al. Streptomyces sp. as a cause of nodular pneumonia in a HIV infected patient? Medical Microbiology Letter 1992; 1:297 – 303. 9. Ahmed AJ, Ali ST, Weinbaum D, Goldberg E. Streptomyces infection in AIDS presenting with pneumonia and monoarthritis. Infectious Diseases in Clinical Practice 1996; 5:207 – 8. 10. Robboy SJ, Vickery AL. Tinctorial and morphologic properties distinguishing actinomycosis and nocardiosis. N Engl J Med 1970; 282: 593 – 6. 11. Green WO, Adams TE. Mycetoma in the United States: a review and report of seven additional cases. Am J Clin Pathol 1964; 42:75 – 91. 12. Hay RJ, Mahgoub ES, Leon G, Al-Sogair S, Welsh O. Mycetoma. J Med Vet Mycol 1992; 30:41 – 9. 13. Shanley JD, Snyder K, Child JS. Chronic pericarditis due to a Streptomyces species. Am J Clin Pathol 1979; 72:107 – 10. 14. Clarke PRR, Warnock GBR, Blowers R, Wilkinson M. Brain abscess due to Streptomyces griseus. J Neurol Neurosurg Psychiatry 1964; 27: 553 – 5. 15. Gruet ML, Maydat, Ferry R. Peritonitis caused by Streptomyces somaliensis [in French]. Bull Soc Med Afr Noire Lang Fr 1970; 15:609 – 10. 16. Mossad SB, Tomford JW, Stewart R, Ratliff NB, Hall GS. Case report of Streptomyces endocarditis of a prosthetic aortic valve. J Clin Microbiol 1995; 33:3335 – 7. 17. Holtz HA, Lavery DP, Kapila R. Actinomycetales infection in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 102:203 – 5. 18. McNeil MM, Brown JM, Jarvis WR, Ajello L. Comparison of species distribution and antimicrobial susceptibility of aerobic actinomycetes from clinical specimens. Rev Infect Dis 1990; 12:778 – 83. 19. Carroll GF, Brown JM, Haley LD. A method for detecting in vitro drug susceptibilities of some Nocardia and Actinomadura. Am J Pathol 1977; 68:279 – 83. 20. Wallace RJ, Septimus EJ, Williams TW. Use of trimethoprim-sulfamethoxazole for treatment of infections due to Nocardia. Rev Infect Dis 1982; 4:315 – 25. cida UC: CID