Undetectable antimicrobial plasma concentrations in an HIV-positive patient with protein-losing enteropathy and chylothorax during Mycobacterium genavense and Leishmania abdominal infections

Undetectable antimicrobial plasma concentrations in an HIV-positive patient with protein-losing... Sir, Mycobacterium genavense (MG) is a ubiquitous microorganism accounting for up to 13% of non-tuberculous mycobacterial infections among advanced HIV-infected patients;1 an increasing incidence in organ transplant recipients and subjects receiving immunosuppressive therapies has recently been reported.2 Its prevalence is probably underestimated, due to non-peculiar features and to specific growth requirements.2 MG shows a strong affinity for the gastrointestinal tract and it may cause focal syndromes, which may develop even after successful chemotherapy.3 Optimal treatment has not been established, although prolonged regimens including macrolides seem to be efficacious;4 notably, 5 year survival has been reported to be as low as 50%.5 Therapeutic drug monitoring has been suggested in selected patients with mycobacterial infections,6 but to our knowledge pharmacokinetic evaluations in patients with MG infections are lacking. Herein we report a case of an HIV-positive patient developing chylous ascites, chylothorax and protein-losing enteropathy after coinfection with MG and Leishmania. A South American man in his mid-40s was admitted to our ward complaining of a long history of abdominal pain, diarrhoea and weight loss and now presenting with shifting abdominal dullness, pancytopenia and massive right pleural effusion (Figure 1b). His past medical history included AIDS (neurotoxoplasmosis, cutaneous Kaposi’s sarcoma and disseminated cytomegalovirus infection 8 years before presentation) with a nadir CD4+ T lymphocyte count of 1 cell/mm3. Despite an incomplete compliance (multiple drug holidays), he maintained HIV-RNA suppression in the last 2 years with an unsatisfactory immunological recovery (4 CD4+ T cells/mm3). Two years before presentation, a diagnosis of disseminated infection with MG and leishmaniasis was made by stool culture (MG), bone marrow biopsy (Leishmania) and abdominal lymph node histology (showing acid-fast bacilli and amastigotes). The patient received liposomal amphotericin B treatment plus clarithromycin, ethambutol, moxifloxacin and rifabutin for 23 months until 1 month before admission. Negative stool cultures at follow-up visits were reported. His HAART regimen included twice-daily darunavir/ritonavir (600/100 mg) and dolutegravir (50 mg); he was also on atovaquone (750 mg) and on maintenance liposomal amphotericin B (3 mg/kg every 21 days). Chylothorax and chylous ascites were diagnosed following pleural effusion and ascites analysis. Traumatic, neoplastic or infective causes were excluded. The right chylothorax was potentially caused by the thoracic duct obstruction due to massive colliquative abdominal lymphadenopathies (Figure 1c), which grew in size despite combined targeted treatment. Lymphoscintigraphy confirmed such a hypothesis (Figure 1a). Low levels of total protein, albumin, pre-albumin and immunoglobulins indicated severe protein-losing enteropathy (liver cirrhosis and proteinuria were excluded). Considering the hypothesis of mesenteric syndrome related to MG infection, we reintroduced clarithromycin (500 mg every 12 h), ethambutol (1200 mg every 24 h) and rifabutin (150 mg on alternate days). Therapeutic drug monitoring analysis (by ultra-HPLC coupled to tandem MS; Waters, Milan, Italy) was performed twice (2 weeks apart) after directly observed therapy at 2, 4 and 6 h post-dose. Antiretroviral and antimycobacterial plasma concentrations were undetectable at every timepoint. Serum albumin supplementation, a low-fat, medium-chain triglyceride, high protein-based diet and midodrine led to partial improvement of drainage output (from 2000 to 150 mL/day). Nevertheless, the patient’s condition deteriorated and 4 months after admission he passed away. Figure 1 View largeDownload slide Dynamic lymphoscintigraphy (a), chest radiography (b) and abdominal CT scan (c). (a) Lymphoscintigraphy at 24 h after technetium-99m albumin nanocolloid injection into the lower limbs revealed lymphatic obstruction at the abdominal level and tracer accumulation around the spleen and liver, with no evidence of lymphatic drainage above the obstruction site. (b) Massive right pleural effusion with chemical–physical properties of a chylothorax. (c) Ascites, intestinal limbs thickening due to wall oedema and massive colliquative mesenteric lymphadenopathies (>7 cm in diameter) compressing and thinning jejunal–ileal veins in the presence of venous collateral circles. Figure 1 View largeDownload slide Dynamic lymphoscintigraphy (a), chest radiography (b) and abdominal CT scan (c). (a) Lymphoscintigraphy at 24 h after technetium-99m albumin nanocolloid injection into the lower limbs revealed lymphatic obstruction at the abdominal level and tracer accumulation around the spleen and liver, with no evidence of lymphatic drainage above the obstruction site. (b) Massive right pleural effusion with chemical–physical properties of a chylothorax. (c) Ascites, intestinal limbs thickening due to wall oedema and massive colliquative mesenteric lymphadenopathies (>7 cm in diameter) compressing and thinning jejunal–ileal veins in the presence of venous collateral circles. It is noteworthy that little is known about factors associated with mortality and complications of non-tuberculous mycobacterial infections; diagnostic and treatment delay, antimicrobial therapy duration, ongoing immune suppression and comorbidities should be carefully considered.2,4,5 Refractory chylothorax complicating chylous ascites is a very rare entity, reported so far in an HIV-positive patient with MG infection (despite antibiotic treatment).7 Retractile mesenteritis may cause chronic inflammation, small bowel wall thickening, mesenteric and retroperitoneal lymphadenopathies and, eventually, obstruction of lymphatic flow.4 It may also lead to malabsorption and irreversible lymphatic vessel disruption.4,7 In our patient, relevant drug–drug interactions were excluded; he was receiving rifabutin that may marginally increase darunavir and decrease dolutegravir concentrations without affecting their efficacy and safety.8,9 Considering the undetectability of plasma concentrations of all drugs in our patient, we believe that malabsorption was the possible underlying cause of this finding and might have contributed to the fatal outcome. Visceral leishmaniasis could have worsened the intestinal damage, enteropathy and lymphatic blockade, as already described.10 Our patient’s multiple comorbidities, frail phenotype, polypharmacy, HIV-RNA undetectability and the observed pleural effusion reduction prevented us from modifying the ongoing therapy and from administering available treatments using the intravenous or intramuscular route. Our case illustrates that MG infection should be suspected as a rare cause of non-malignant chylothorax even after specific treatment. It also emphasizes that confirmed pharmacokinetic evaluations should be considered in patients with slow response to treatment, relapses or gut-affecting conditions potentially hampering drug absorption; rapid pharmacokinetic results and team management (including gastroenterologists, pharmacologists and infectious disease consultants) are warranted for selected complex patients. In case of suboptimal exposure, alternative drugs, doses or ways of administration need to be implemented. Funding This study was conducted as part of our routine work. Transparency declarations None to declare. References 1 Pechère M, Opravil M, Wald A et al.   Clinical and epidemiologic features of infection with Mycobacterium genavense. Swiss HIV Cohort Study. Arch Intern Med  1995; 155: 400– 4. Google Scholar CrossRef Search ADS PubMed  2 Santos M, Gil-Brusola A, Escandell A et al.   Mycobacterium genavense infections in a tertiary hospital and reviewed cases in non-HIV patients. Patholog Res Int  2014; 2014: 371370. Google Scholar PubMed  3 Borde JP, Offensperger WB, Kern WV et al.   Mycobacterium genavense specific mesenteritic syndrome in HIV-infected patients: a new entity of retractile mesenteritis? AIDS  2013; 27: 2819– 22. Google Scholar CrossRef Search ADS PubMed  4 Esteban J, García-Pedrazuela M, Muñoz-Egea MC et al.   Current treatment of nontuberculous mycobacteriosis: an update. Expert Opin Pharmacother  2012; 13: 967– 86. Google Scholar CrossRef Search ADS PubMed  5 Charles P, Lortholary O, Dechartres A et al.   Mycobacterium genavense infections: a retrospective multicenter study in France, 1996-2007. Medicine (Baltimore)  2011; 90: 223– 30. Google Scholar CrossRef Search ADS PubMed  6 Koh WJ, Jeong BH, Jeon K et al.   Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med  2012; 186: 797– 802. Google Scholar CrossRef Search ADS PubMed  7 Tanaka T, Saito N, Takaki M et al.   Refractory chylothorax in HIV/AIDS-related disseminated mycobacterial infection. Thorax  2016; 71: 960– 1. Google Scholar CrossRef Search ADS PubMed  8 Sekar V, Lavreys L, Van de Casteele T et al.   Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers. Antimicrob Agents Chemother  2010; 54: 4440– 5. Google Scholar CrossRef Search ADS PubMed  9 Dooley KE, Sayre P, Borland J et al.   Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr  2013; 62: 21– 7. Google Scholar CrossRef Search ADS PubMed  10 Hicks L, Kant P, Tay PH et al.   Visceral leishmaniasis presenting with intestinal failure: a case report and literature review. Eur J Gastroenterol Hepatol  2009; 21: 117– 22. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Undetectable antimicrobial plasma concentrations in an HIV-positive patient with protein-losing enteropathy and chylothorax during Mycobacterium genavense and Leishmania abdominal infections

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0305-7453
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1460-2091
D.O.I.
10.1093/jac/dkx385
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Abstract

Sir, Mycobacterium genavense (MG) is a ubiquitous microorganism accounting for up to 13% of non-tuberculous mycobacterial infections among advanced HIV-infected patients;1 an increasing incidence in organ transplant recipients and subjects receiving immunosuppressive therapies has recently been reported.2 Its prevalence is probably underestimated, due to non-peculiar features and to specific growth requirements.2 MG shows a strong affinity for the gastrointestinal tract and it may cause focal syndromes, which may develop even after successful chemotherapy.3 Optimal treatment has not been established, although prolonged regimens including macrolides seem to be efficacious;4 notably, 5 year survival has been reported to be as low as 50%.5 Therapeutic drug monitoring has been suggested in selected patients with mycobacterial infections,6 but to our knowledge pharmacokinetic evaluations in patients with MG infections are lacking. Herein we report a case of an HIV-positive patient developing chylous ascites, chylothorax and protein-losing enteropathy after coinfection with MG and Leishmania. A South American man in his mid-40s was admitted to our ward complaining of a long history of abdominal pain, diarrhoea and weight loss and now presenting with shifting abdominal dullness, pancytopenia and massive right pleural effusion (Figure 1b). His past medical history included AIDS (neurotoxoplasmosis, cutaneous Kaposi’s sarcoma and disseminated cytomegalovirus infection 8 years before presentation) with a nadir CD4+ T lymphocyte count of 1 cell/mm3. Despite an incomplete compliance (multiple drug holidays), he maintained HIV-RNA suppression in the last 2 years with an unsatisfactory immunological recovery (4 CD4+ T cells/mm3). Two years before presentation, a diagnosis of disseminated infection with MG and leishmaniasis was made by stool culture (MG), bone marrow biopsy (Leishmania) and abdominal lymph node histology (showing acid-fast bacilli and amastigotes). The patient received liposomal amphotericin B treatment plus clarithromycin, ethambutol, moxifloxacin and rifabutin for 23 months until 1 month before admission. Negative stool cultures at follow-up visits were reported. His HAART regimen included twice-daily darunavir/ritonavir (600/100 mg) and dolutegravir (50 mg); he was also on atovaquone (750 mg) and on maintenance liposomal amphotericin B (3 mg/kg every 21 days). Chylothorax and chylous ascites were diagnosed following pleural effusion and ascites analysis. Traumatic, neoplastic or infective causes were excluded. The right chylothorax was potentially caused by the thoracic duct obstruction due to massive colliquative abdominal lymphadenopathies (Figure 1c), which grew in size despite combined targeted treatment. Lymphoscintigraphy confirmed such a hypothesis (Figure 1a). Low levels of total protein, albumin, pre-albumin and immunoglobulins indicated severe protein-losing enteropathy (liver cirrhosis and proteinuria were excluded). Considering the hypothesis of mesenteric syndrome related to MG infection, we reintroduced clarithromycin (500 mg every 12 h), ethambutol (1200 mg every 24 h) and rifabutin (150 mg on alternate days). Therapeutic drug monitoring analysis (by ultra-HPLC coupled to tandem MS; Waters, Milan, Italy) was performed twice (2 weeks apart) after directly observed therapy at 2, 4 and 6 h post-dose. Antiretroviral and antimycobacterial plasma concentrations were undetectable at every timepoint. Serum albumin supplementation, a low-fat, medium-chain triglyceride, high protein-based diet and midodrine led to partial improvement of drainage output (from 2000 to 150 mL/day). Nevertheless, the patient’s condition deteriorated and 4 months after admission he passed away. Figure 1 View largeDownload slide Dynamic lymphoscintigraphy (a), chest radiography (b) and abdominal CT scan (c). (a) Lymphoscintigraphy at 24 h after technetium-99m albumin nanocolloid injection into the lower limbs revealed lymphatic obstruction at the abdominal level and tracer accumulation around the spleen and liver, with no evidence of lymphatic drainage above the obstruction site. (b) Massive right pleural effusion with chemical–physical properties of a chylothorax. (c) Ascites, intestinal limbs thickening due to wall oedema and massive colliquative mesenteric lymphadenopathies (>7 cm in diameter) compressing and thinning jejunal–ileal veins in the presence of venous collateral circles. Figure 1 View largeDownload slide Dynamic lymphoscintigraphy (a), chest radiography (b) and abdominal CT scan (c). (a) Lymphoscintigraphy at 24 h after technetium-99m albumin nanocolloid injection into the lower limbs revealed lymphatic obstruction at the abdominal level and tracer accumulation around the spleen and liver, with no evidence of lymphatic drainage above the obstruction site. (b) Massive right pleural effusion with chemical–physical properties of a chylothorax. (c) Ascites, intestinal limbs thickening due to wall oedema and massive colliquative mesenteric lymphadenopathies (>7 cm in diameter) compressing and thinning jejunal–ileal veins in the presence of venous collateral circles. It is noteworthy that little is known about factors associated with mortality and complications of non-tuberculous mycobacterial infections; diagnostic and treatment delay, antimicrobial therapy duration, ongoing immune suppression and comorbidities should be carefully considered.2,4,5 Refractory chylothorax complicating chylous ascites is a very rare entity, reported so far in an HIV-positive patient with MG infection (despite antibiotic treatment).7 Retractile mesenteritis may cause chronic inflammation, small bowel wall thickening, mesenteric and retroperitoneal lymphadenopathies and, eventually, obstruction of lymphatic flow.4 It may also lead to malabsorption and irreversible lymphatic vessel disruption.4,7 In our patient, relevant drug–drug interactions were excluded; he was receiving rifabutin that may marginally increase darunavir and decrease dolutegravir concentrations without affecting their efficacy and safety.8,9 Considering the undetectability of plasma concentrations of all drugs in our patient, we believe that malabsorption was the possible underlying cause of this finding and might have contributed to the fatal outcome. Visceral leishmaniasis could have worsened the intestinal damage, enteropathy and lymphatic blockade, as already described.10 Our patient’s multiple comorbidities, frail phenotype, polypharmacy, HIV-RNA undetectability and the observed pleural effusion reduction prevented us from modifying the ongoing therapy and from administering available treatments using the intravenous or intramuscular route. Our case illustrates that MG infection should be suspected as a rare cause of non-malignant chylothorax even after specific treatment. It also emphasizes that confirmed pharmacokinetic evaluations should be considered in patients with slow response to treatment, relapses or gut-affecting conditions potentially hampering drug absorption; rapid pharmacokinetic results and team management (including gastroenterologists, pharmacologists and infectious disease consultants) are warranted for selected complex patients. In case of suboptimal exposure, alternative drugs, doses or ways of administration need to be implemented. Funding This study was conducted as part of our routine work. Transparency declarations None to declare. References 1 Pechère M, Opravil M, Wald A et al.   Clinical and epidemiologic features of infection with Mycobacterium genavense. Swiss HIV Cohort Study. Arch Intern Med  1995; 155: 400– 4. Google Scholar CrossRef Search ADS PubMed  2 Santos M, Gil-Brusola A, Escandell A et al.   Mycobacterium genavense infections in a tertiary hospital and reviewed cases in non-HIV patients. Patholog Res Int  2014; 2014: 371370. Google Scholar PubMed  3 Borde JP, Offensperger WB, Kern WV et al.   Mycobacterium genavense specific mesenteritic syndrome in HIV-infected patients: a new entity of retractile mesenteritis? AIDS  2013; 27: 2819– 22. Google Scholar CrossRef Search ADS PubMed  4 Esteban J, García-Pedrazuela M, Muñoz-Egea MC et al.   Current treatment of nontuberculous mycobacteriosis: an update. Expert Opin Pharmacother  2012; 13: 967– 86. Google Scholar CrossRef Search ADS PubMed  5 Charles P, Lortholary O, Dechartres A et al.   Mycobacterium genavense infections: a retrospective multicenter study in France, 1996-2007. Medicine (Baltimore)  2011; 90: 223– 30. Google Scholar CrossRef Search ADS PubMed  6 Koh WJ, Jeong BH, Jeon K et al.   Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med  2012; 186: 797– 802. Google Scholar CrossRef Search ADS PubMed  7 Tanaka T, Saito N, Takaki M et al.   Refractory chylothorax in HIV/AIDS-related disseminated mycobacterial infection. Thorax  2016; 71: 960– 1. Google Scholar CrossRef Search ADS PubMed  8 Sekar V, Lavreys L, Van de Casteele T et al.   Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers. Antimicrob Agents Chemother  2010; 54: 4440– 5. Google Scholar CrossRef Search ADS PubMed  9 Dooley KE, Sayre P, Borland J et al.   Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr  2013; 62: 21– 7. Google Scholar CrossRef Search ADS PubMed  10 Hicks L, Kant P, Tay PH et al.   Visceral leishmaniasis presenting with intestinal failure: a case report and literature review. Eur J Gastroenterol Hepatol  2009; 21: 117– 22. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 1, 2018

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