JAC
Research letters
Funding This work was supported by internal funding.
Transparency declarations None to declare.
References 1 Lopez-Novoa JM, Quiros Y, Vicente L et al. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 2011; 79: 33– 45. 2 Williams PD, Bennett DB, Gleason CR et al. Correlation between renal membrane binding and nephrotoxicity of aminoglycosides. Antimicrob Agents Chemother 1987; 31: 570– 4. 3 Gilbert DN, Plamp C, Starr P et al. Comparative nephrotoxicity of gentamicin and tobramycin in rats. Antimicrob Agents Chemother 1978; 13: 34 –40. 4 Smith CR, Lipsky JJ, Laskin OL et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 1980; 302: 1106– 9. 5 Barza M, Ioannidis JP, Cappelleri JC et al. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312: 338– 45. 6 Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70. 7 Bellomo R, Ronco C, Kellum JA et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–12.
J Antimicrob Chemother 2014 doi:10.1093/jac/dku138 Advance Access publication 30 April 2014
Sepedonium intra-abdominal infection: a case report and review of an emerging fungal infection Norihiro Yogo1*, Leland Shapiro1,2 and Kristine M. Erlandson1 1
Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Division of Infectious Diseases, Department of Medicine, Denver Veterans Affairs Medical Center, Denver, CO, USA *Corresponding author. Tel: +1-303-724-4941; Fax: +1-303-724-4926; E-mail: [email protected]
Keywords: peritonitis, peritoneal dialysis, diabetes mellitus,
environmental fungus Sir, Sepedonium is an environmental fungus that is not considered to be a cause of human disease. We present, along with a review of the literature, a unique case of a man with localized, recalcitrant, intra-abdominal Sepedonium infection. A man in his 60s with congestive heart failure, poorly controlled diabetes mellitus type I and end-stage renal disease on peritoneal dialysis presented to our institution with abdominal pain and a cloudy peritoneal dialysate. Peritoneal dialysate analysis revealed 4000 white blood cells/mL with 80% neutrophils and a negative Gram stain. A CT scan of the abdomen and pelvis showed a 6.6×6.8 cm fluid collection near the tip of the peritoneal dialysis catheter. The catheter was removed on hospital Day 5, and on Day 7 a colony of mould grew from catheter tip and peritoneal fluid specimens. Early growth on fungal medium (Sabouraud Dextrose Agar pH 5.6; Thermo Fischer Scientific, Lenexa, KS, USA) raised a suggestion of Scedosporium spp. and oral voriconazole was initiated. However, the patient developed delirium and visual hallucinations, prompting a change to 5 mg/kg liposomal amphotericin B intravenously daily on hospital Day 11. Upon maturation, the mould was woolly white with a light brown underside (Figure 1a). Microscopy revealed septated hyphae with spherical, thick-walled conidia consistent with Sepedonium (Figure 1b). A DNA probe for Histoplasma capsulatum was negative and Sepedonium was confirmed by a reference laboratory. On hospital Day 13, the right lower quadrant fluid collection was drained percutaneously and a drainage catheter was placed, with cultures again yielding Sepedonium. The percutaneous catheter was removed after 1 week due to a low output. However, 3 days after catheter removal, the patient had recurrent abdominal pain and a repeat CT showed a reaccumulation of fluid measuring 5.7×4.2 cm. Repeat fluid drainage and fungal cultures revealed Sepedonium despite 2 weeks of liposomal amphotericin B treatment. Since comorbidities precluded surgical debridement, five percutaneous drainage procedures were performed to remove fluid
2583
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on April 28, 2015
alter after correction for difference in the baseline eGFR. Mean increases in serum creatinine were 13.3 nmol/mL for gentamicin and 0.1 nmol/mL for tobramycin (P ¼ 0.02). The relative decrease in eGFR between the groups showed a trend of a higher loss of eGFR for patients given gentamicin (4.8% versus 1%, P ¼ 0.07). This large retrospective study shows that ODD gentamicin is more nephrotoxic than ODD tobramycin in infected patients treated with an aminoglycoside for ≥3 days. To our knowledge, this is the first study directly comparing the nephrotoxic potential of these two most frequently used aminoglycosides. Despite the retrospective design with consecutive cohorts, the risks of both selection and time bias appear low since, per criterion, similar numbers of patients were excluded and there were no significant differences between characteristics of both included and eligible patients (data not shown for the latter). The validity of our outcomes is strengthened by the large cohort investigated and the hospital-wide switch to tobramycin in all aminoglycoside indications. Nevertheless, future prospective randomized studies remain warranted to confirm these results. In conclusion, our data suggest that in the once-daily dosing era, a further reduction of the incidence of nephrotoxicity may be obtained by preferring tobramycin over gentamicin as first-line aminoglycoside in infected patients.
Research letters
(a)
(b)
that reaccumulated within a thick-walled cavity after each attempt at catheter removal. After 5 weeks of amphotericin B, fluid cultures were sterile, although 15 weeks of therapy was required for clinical resolution. Sepedonium is an environmental organism that is considered a contaminant in clinical microbiological specimens and not considered a cause of human disease.1,2 Morphologically, Sepedonium resembles H. capsulatum but Sepedonium is not dimorphic.1 Diagnosis is based on morphology and a negative DNA probe for H. capsulatum. 1 A literature review revealed only two previous cases of Sepedonium implicated in human disease.3,4 The first reported case, in 1934, described a middle-aged man with a progressive ulcerative dermatitis and lymphadenitis.3 Post mortem analysis revealed yeast-like organisms in the lung and caseating granulomas in the adrenal glands. In retrospect, this clinical presentation along with the presence of yeast within the phagocytes suggested a diagnosis of H. capsulatum as opposed to Sepedonium. The second reported case, in 2003, was in a 43-year-old man with a new diagnosis of AIDS.4 He presented with a CD4 lymphocyte count of 31 cells/mL and erythematous papular skin lesions. Skin biopsy and blood cultures were positive for Sepedonium. The patient was treated with oral itraconazole and initiation of antiretroviral therapy, with resolution of his skin lesions. The limited clinical literature and extremely rare occurrence of Sepedonium infections strongly suggest this is an opportunistic organism affecting persons with impaired immunity. Our patient had uncontrolled diabetes mellitus and end-stage renal disease requiring peritoneal dialysis. The peritoneal dialysis catheter was a likely portal of entry and enabled a persistent localized infection. Although the fungus was considered to be a true pathogen early in the clinical presentation, contamination of the specimen was also considered. However, the recovery of this organism from repeated fluid aspirations and the exchange of catheters between samples made contamination during specimen collection unlikely. Contamination at the laboratory level was also considered, but the absence of other reports of Sepedonium at our institution during this time made this unlikely. There are no established antifungal susceptibility breakpoints for Sepedonium. Given microbiological similarities to Histoplasma and underlying congestive heart failure precluding the use of
2584
itraconazole, our patient was treated with liposomal amphotericin B. The duration of therapy was based on the patient’s clinical response and extrapolated from treatment guidelines for histoplasmosis.5 The persistence of tenacious fluid in the abscess cavity despite antifungal therapy and repeated aspirations suggests that surgical debridement may be required for a cure of localized Sepedonium infections. In summary, we describe a case of persistent intra-abdominal infection due to Sepedonium, an environmental fungus not considered to cause human disease. Opportunities for environmental organisms to become emerging pathogens are enhanced by the increasing prevalence of immunosuppressing conditions such as AIDS6 and diabetes mellitus,7 and by the more widespread use of invasive and semi-invasive procedures (exemplified by the recent outbreak of Exserohilum related to contaminated steroid injections8). Clinicians should be aware of the potential for infections caused by Sepedonium in susceptible hosts.
Funding This study was carried out as part of our routine work.
Transparency declarations None to declare.
References 1 Larone DH. Medically Important Fungi: A Guide to Identification. 4th edn. Washington, DC: American Society for Microbiology Press, 2002. 2 St-Germain G, Rummerbell R. Identifying Fungi: A Clinical Laboratory Handbook. 2nd edn. Belmont, CA: Star Publishing Company, 2010. 3 Hansmann GH, Schenken JR. A unique infection in man caused by a new yeast-like organism, a pathogenic member of the genus Sepedonium. Am J Pathol 1934; 10: 731–8.7. 4 Ng KP, Soo-Hoo TS, Na SL et al. Sepedonium species: an emerging opportunistic fungal infection in a patient with AIDS. Clinical Microbiology Newsletter 2003; 25: 20– 2.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on April 28, 2015
Figure 1. (a) Sepedonium on fungal medium (Sabouraud Dextrose Agar pH 5.6; Thermo Fischer Scientific, Lenexa, KS, USA), showing woolly white growth with a light brown underside. (b) Microscopic view of Sepedonium showing round, thick-walled, knobby conidia in a background of septated hyphae. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Research letters
5 Wheat LJ, Freifeld AG, Kleiman MB et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45: 807–25. 6 CDC. HIV Surveillance Report, 2011; vol. 23. February 2013. http://www. cdc.gov/hiv/topics/surveillance/resources/reports/ (7 November 2013, date last accessed). 7 CDC. Diabetes Data & Trends. March 2013. http://www.cdc.gov/diabetes/ statistics/prev/national/figpersons.htm (7 November 2013, date last accessed).
J Antimicrob Chemother 2014 doi:10.1093/jac/dku169 Advance Access publication 15 May 2014
Intra-abdominal penetration and pharmacodynamic exposure to fluconazole in three liver transplant patients with deep-seated candidiasis Federico Pea1,2*, Elda Righi3, Piergiorgio Cojutti1,2, Alessia Carnelutti4, Umberto Baccarani5, Giorgio Soardo4 and Matteo Bassetti3 1
Institute of Clinical Pharmacology, Azienda OspedalieroUniversitaria Santa Maria della Misericordia, Udine, Italy; 2 Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; 3Clinic of Infectious Diseases, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy; 4Clinic of Internal Medicine-Liver Unit, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; 5Department of Medical and Biological Sciences, University of Udine, Udine, Italy *Corresponding author. Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy. Tel: +39-0432-559833; E-mail: [email protected]
Keywords: pharmacokinetic/pharmacodynamic, bile, ascites
Sir, Invasive candidiasis is a major cause of mortality and morbidity after liver transplantation (LTx).1 Immunosuppression may predispose transplant patients to infections, and in the specific context of LTx recipients the surgically reconstructed biliary tract may represent a primary site for infectious complications. It has been shown that the impairment of bile excretion, a frequent condition in LTx patients, may increase the likelihood of developing invasive fungal cholangitis.2 Additionally, invasive candidiasis may be commonly associated with peritonitis in these patients.1 Fluconazole is presently the drug of first choice for the treatment of intra-abdominal candidiasis in those patients who are not critically ill and who have no specific risk factors or previous azole exposure.3
To our knowledge, no data on intra-abdominal fluconazole exposure in LTx patients have been published. Here we report on the intra-abdominal penetration and pharmacodynamic exposure in three LTx patients who had documented intra-abdominal candidiasis (cholangitis in Patients 1 and 2; peritonitis in Patient 3) treated with fluconazole. Informed consent for bile or ascites and blood sampling was obtained from the patients. Single bile samples (from a T-tube that was used for splinting the biliary anastomosis between the donor’s and the recipient’s bile ducts) or ascites samples (during diagnostic paracentesis) and simultaneous blood samples (from the antecubital vein) were collected at steady-state just before the daily fluconazole administration for assay of trough concentrations (Cmin). Plasma, ascites and bile fluconazole concentrations were measured by means of a validated HPLC technique,4 with some modifications. At the Institute of Clinical Pharmacology fluconazole dosages are routinely adjusted in real time by therapeutic drug monitoring (TDM) in LTx patients, with the intent of maintaining plasma Cmin at around 10 –15 mg/L. This approach should ensure an AUC/MIC ratio of .1005,6 against all fluconazole-susceptible strains of Candida (MIC ≤2 mg/L).7 Briefly, Patient 1 (60–70 years, 60–70 kg and serum creatinine 1.2 mg/dL) and Patient 2 (60 – 70 years, 60 – 70 kg and serum creatinine 1.18 mg/dL) had a diagnosis of Candida cholangitis at 14 days and 30 months post-transplant, respectively. Candida albicans strains susceptible to fluconazole (MIC 0.25 mg/L; Sensitire YeastOne colorimetric MIC procedure) were isolated from the biliary drainage of both patients. Intravenous fluconazole was started with a 400 mg loading dose, followed by TDM-guided maintenance dosages (200 mg daily reduced to 100 mg daily from day 10 for Patient 1; 200 mg daily for the whole treatment period for Patient 2). Fluconazole bile and plasma Cmin (Table 1) were 9.04 and 17.81 mg/L, respectively at therapy day 9 for Patient 1, and 6.29 and 12.61 mg/L at therapy day 5 for Patient 2. Patient 3 (60–70 years, 60–70 kg and serum creatinine 1.7 mg/dL) developed Candida peritonitis at day 62 post-transplant, after a history of recurrent, refractory ascites. Cultures from ascites yielded C. albicans susceptible to fluconazole (MIC 0.25 mg/L; Sensitire YeastOne colorimetric MIC procedure). Intravenous fluconazole was started with a 400 mg loading dose followed by a maintenance dose of 150 mg daily, then reduced to 100 mg daily from day 8. Fluconazole Cmin in ascites and plasma at therapy day 5 was 9.60 and 11.30 mg/L, respectively (Table 2). The fluconazole bile-to-plasma ratios of Cmin in the two LTx patients with cholangitis (0.50 and 0.51) were lower than previously observed in a non-LTx patient with Candida cholecystitis (around 1.2 at therapy day 5 by visual inspection).8 Conversely, the ascites-to-plasma ratio of Cmin in the LTx patient with peritonitis (0.85) was similar to that observed in a non-LTx cirrhotic patient with Candida peritonitis (0.81 at 3 h post-dose at therapy day 5).9 Interestingly, 14 days of fluconazole treatment with maintenance of plasma Cmin at around 15 mg/L resulted in clinical resolution of intra-abdominal candidiasis in all three LTx patients with no evidence of recurrence at 30 days of follow-up. It should be noticed that, thanks to TDM, in these particular patients successful treatment was based on doses of fluconazole much lower (100 – 200 mg/day) than those usually administered for systemic infections (400–800 mg/day).6 Previous studies showed that the AUC/MIC ratio is the pharmacodynamic parameter that best correlates with fluconazole efficacy,5,10 and the recent
2585
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on April 28, 2015
8 CDC. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep 2012; 61: 839–42.
JAC
Research letters
Funding This work was supported by internal funding.
Transparency declarations None to declare.
References 1 Lopez-Novoa JM, Quiros Y, Vicente L et al. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 2011; 79: 33– 45. 2 Williams PD, Bennett DB, Gleason CR et al. Correlation between renal membrane binding and nephrotoxicity of aminoglycosides. Antimicrob Agents Chemother 1987; 31: 570– 4. 3 Gilbert DN, Plamp C, Starr P et al. Comparative nephrotoxicity of gentamicin and tobramycin in rats. Antimicrob Agents Chemother 1978; 13: 34 –40. 4 Smith CR, Lipsky JJ, Laskin OL et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 1980; 302: 1106– 9. 5 Barza M, Ioannidis JP, Cappelleri JC et al. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312: 338– 45. 6 Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70. 7 Bellomo R, Ronco C, Kellum JA et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–12.
J Antimicrob Chemother 2014 doi:10.1093/jac/dku138 Advance Access publication 30 April 2014
Sepedonium intra-abdominal infection: a case report and review of an emerging fungal infection Norihiro Yogo1*, Leland Shapiro1,2 and Kristine M. Erlandson1 1
Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Division of Infectious Diseases, Department of Medicine, Denver Veterans Affairs Medical Center, Denver, CO, USA *Corresponding author. Tel: +1-303-724-4941; Fax: +1-303-724-4926; E-mail: [email protected]
Keywords: peritonitis, peritoneal dialysis, diabetes mellitus,
environmental fungus Sir, Sepedonium is an environmental fungus that is not considered to be a cause of human disease. We present, along with a review of the literature, a unique case of a man with localized, recalcitrant, intra-abdominal Sepedonium infection. A man in his 60s with congestive heart failure, poorly controlled diabetes mellitus type I and end-stage renal disease on peritoneal dialysis presented to our institution with abdominal pain and a cloudy peritoneal dialysate. Peritoneal dialysate analysis revealed 4000 white blood cells/mL with 80% neutrophils and a negative Gram stain. A CT scan of the abdomen and pelvis showed a 6.6×6.8 cm fluid collection near the tip of the peritoneal dialysis catheter. The catheter was removed on hospital Day 5, and on Day 7 a colony of mould grew from catheter tip and peritoneal fluid specimens. Early growth on fungal medium (Sabouraud Dextrose Agar pH 5.6; Thermo Fischer Scientific, Lenexa, KS, USA) raised a suggestion of Scedosporium spp. and oral voriconazole was initiated. However, the patient developed delirium and visual hallucinations, prompting a change to 5 mg/kg liposomal amphotericin B intravenously daily on hospital Day 11. Upon maturation, the mould was woolly white with a light brown underside (Figure 1a). Microscopy revealed septated hyphae with spherical, thick-walled conidia consistent with Sepedonium (Figure 1b). A DNA probe for Histoplasma capsulatum was negative and Sepedonium was confirmed by a reference laboratory. On hospital Day 13, the right lower quadrant fluid collection was drained percutaneously and a drainage catheter was placed, with cultures again yielding Sepedonium. The percutaneous catheter was removed after 1 week due to a low output. However, 3 days after catheter removal, the patient had recurrent abdominal pain and a repeat CT showed a reaccumulation of fluid measuring 5.7×4.2 cm. Repeat fluid drainage and fungal cultures revealed Sepedonium despite 2 weeks of liposomal amphotericin B treatment. Since comorbidities precluded surgical debridement, five percutaneous drainage procedures were performed to remove fluid
2583
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on April 28, 2015
alter after correction for difference in the baseline eGFR. Mean increases in serum creatinine were 13.3 nmol/mL for gentamicin and 0.1 nmol/mL for tobramycin (P ¼ 0.02). The relative decrease in eGFR between the groups showed a trend of a higher loss of eGFR for patients given gentamicin (4.8% versus 1%, P ¼ 0.07). This large retrospective study shows that ODD gentamicin is more nephrotoxic than ODD tobramycin in infected patients treated with an aminoglycoside for ≥3 days. To our knowledge, this is the first study directly comparing the nephrotoxic potential of these two most frequently used aminoglycosides. Despite the retrospective design with consecutive cohorts, the risks of both selection and time bias appear low since, per criterion, similar numbers of patients were excluded and there were no significant differences between characteristics of both included and eligible patients (data not shown for the latter). The validity of our outcomes is strengthened by the large cohort investigated and the hospital-wide switch to tobramycin in all aminoglycoside indications. Nevertheless, future prospective randomized studies remain warranted to confirm these results. In conclusion, our data suggest that in the once-daily dosing era, a further reduction of the incidence of nephrotoxicity may be obtained by preferring tobramycin over gentamicin as first-line aminoglycoside in infected patients.
Research letters
(a)
(b)
that reaccumulated within a thick-walled cavity after each attempt at catheter removal. After 5 weeks of amphotericin B, fluid cultures were sterile, although 15 weeks of therapy was required for clinical resolution. Sepedonium is an environmental organism that is considered a contaminant in clinical microbiological specimens and not considered a cause of human disease.1,2 Morphologically, Sepedonium resembles H. capsulatum but Sepedonium is not dimorphic.1 Diagnosis is based on morphology and a negative DNA probe for H. capsulatum. 1 A literature review revealed only two previous cases of Sepedonium implicated in human disease.3,4 The first reported case, in 1934, described a middle-aged man with a progressive ulcerative dermatitis and lymphadenitis.3 Post mortem analysis revealed yeast-like organisms in the lung and caseating granulomas in the adrenal glands. In retrospect, this clinical presentation along with the presence of yeast within the phagocytes suggested a diagnosis of H. capsulatum as opposed to Sepedonium. The second reported case, in 2003, was in a 43-year-old man with a new diagnosis of AIDS.4 He presented with a CD4 lymphocyte count of 31 cells/mL and erythematous papular skin lesions. Skin biopsy and blood cultures were positive for Sepedonium. The patient was treated with oral itraconazole and initiation of antiretroviral therapy, with resolution of his skin lesions. The limited clinical literature and extremely rare occurrence of Sepedonium infections strongly suggest this is an opportunistic organism affecting persons with impaired immunity. Our patient had uncontrolled diabetes mellitus and end-stage renal disease requiring peritoneal dialysis. The peritoneal dialysis catheter was a likely portal of entry and enabled a persistent localized infection. Although the fungus was considered to be a true pathogen early in the clinical presentation, contamination of the specimen was also considered. However, the recovery of this organism from repeated fluid aspirations and the exchange of catheters between samples made contamination during specimen collection unlikely. Contamination at the laboratory level was also considered, but the absence of other reports of Sepedonium at our institution during this time made this unlikely. There are no established antifungal susceptibility breakpoints for Sepedonium. Given microbiological similarities to Histoplasma and underlying congestive heart failure precluding the use of
2584
itraconazole, our patient was treated with liposomal amphotericin B. The duration of therapy was based on the patient’s clinical response and extrapolated from treatment guidelines for histoplasmosis.5 The persistence of tenacious fluid in the abscess cavity despite antifungal therapy and repeated aspirations suggests that surgical debridement may be required for a cure of localized Sepedonium infections. In summary, we describe a case of persistent intra-abdominal infection due to Sepedonium, an environmental fungus not considered to cause human disease. Opportunities for environmental organisms to become emerging pathogens are enhanced by the increasing prevalence of immunosuppressing conditions such as AIDS6 and diabetes mellitus,7 and by the more widespread use of invasive and semi-invasive procedures (exemplified by the recent outbreak of Exserohilum related to contaminated steroid injections8). Clinicians should be aware of the potential for infections caused by Sepedonium in susceptible hosts.
Funding This study was carried out as part of our routine work.
Transparency declarations None to declare.
References 1 Larone DH. Medically Important Fungi: A Guide to Identification. 4th edn. Washington, DC: American Society for Microbiology Press, 2002. 2 St-Germain G, Rummerbell R. Identifying Fungi: A Clinical Laboratory Handbook. 2nd edn. Belmont, CA: Star Publishing Company, 2010. 3 Hansmann GH, Schenken JR. A unique infection in man caused by a new yeast-like organism, a pathogenic member of the genus Sepedonium. Am J Pathol 1934; 10: 731–8.7. 4 Ng KP, Soo-Hoo TS, Na SL et al. Sepedonium species: an emerging opportunistic fungal infection in a patient with AIDS. Clinical Microbiology Newsletter 2003; 25: 20– 2.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on April 28, 2015
Figure 1. (a) Sepedonium on fungal medium (Sabouraud Dextrose Agar pH 5.6; Thermo Fischer Scientific, Lenexa, KS, USA), showing woolly white growth with a light brown underside. (b) Microscopic view of Sepedonium showing round, thick-walled, knobby conidia in a background of septated hyphae. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Research letters
5 Wheat LJ, Freifeld AG, Kleiman MB et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45: 807–25. 6 CDC. HIV Surveillance Report, 2011; vol. 23. February 2013. http://www. cdc.gov/hiv/topics/surveillance/resources/reports/ (7 November 2013, date last accessed). 7 CDC. Diabetes Data & Trends. March 2013. http://www.cdc.gov/diabetes/ statistics/prev/national/figpersons.htm (7 November 2013, date last accessed).
J Antimicrob Chemother 2014 doi:10.1093/jac/dku169 Advance Access publication 15 May 2014
Intra-abdominal penetration and pharmacodynamic exposure to fluconazole in three liver transplant patients with deep-seated candidiasis Federico Pea1,2*, Elda Righi3, Piergiorgio Cojutti1,2, Alessia Carnelutti4, Umberto Baccarani5, Giorgio Soardo4 and Matteo Bassetti3 1
Institute of Clinical Pharmacology, Azienda OspedalieroUniversitaria Santa Maria della Misericordia, Udine, Italy; 2 Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; 3Clinic of Infectious Diseases, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy; 4Clinic of Internal Medicine-Liver Unit, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; 5Department of Medical and Biological Sciences, University of Udine, Udine, Italy *Corresponding author. Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy. Tel: +39-0432-559833; E-mail: [email protected]
Keywords: pharmacokinetic/pharmacodynamic, bile, ascites
Sir, Invasive candidiasis is a major cause of mortality and morbidity after liver transplantation (LTx).1 Immunosuppression may predispose transplant patients to infections, and in the specific context of LTx recipients the surgically reconstructed biliary tract may represent a primary site for infectious complications. It has been shown that the impairment of bile excretion, a frequent condition in LTx patients, may increase the likelihood of developing invasive fungal cholangitis.2 Additionally, invasive candidiasis may be commonly associated with peritonitis in these patients.1 Fluconazole is presently the drug of first choice for the treatment of intra-abdominal candidiasis in those patients who are not critically ill and who have no specific risk factors or previous azole exposure.3
To our knowledge, no data on intra-abdominal fluconazole exposure in LTx patients have been published. Here we report on the intra-abdominal penetration and pharmacodynamic exposure in three LTx patients who had documented intra-abdominal candidiasis (cholangitis in Patients 1 and 2; peritonitis in Patient 3) treated with fluconazole. Informed consent for bile or ascites and blood sampling was obtained from the patients. Single bile samples (from a T-tube that was used for splinting the biliary anastomosis between the donor’s and the recipient’s bile ducts) or ascites samples (during diagnostic paracentesis) and simultaneous blood samples (from the antecubital vein) were collected at steady-state just before the daily fluconazole administration for assay of trough concentrations (Cmin). Plasma, ascites and bile fluconazole concentrations were measured by means of a validated HPLC technique,4 with some modifications. At the Institute of Clinical Pharmacology fluconazole dosages are routinely adjusted in real time by therapeutic drug monitoring (TDM) in LTx patients, with the intent of maintaining plasma Cmin at around 10 –15 mg/L. This approach should ensure an AUC/MIC ratio of .1005,6 against all fluconazole-susceptible strains of Candida (MIC ≤2 mg/L).7 Briefly, Patient 1 (60–70 years, 60–70 kg and serum creatinine 1.2 mg/dL) and Patient 2 (60 – 70 years, 60 – 70 kg and serum creatinine 1.18 mg/dL) had a diagnosis of Candida cholangitis at 14 days and 30 months post-transplant, respectively. Candida albicans strains susceptible to fluconazole (MIC 0.25 mg/L; Sensitire YeastOne colorimetric MIC procedure) were isolated from the biliary drainage of both patients. Intravenous fluconazole was started with a 400 mg loading dose, followed by TDM-guided maintenance dosages (200 mg daily reduced to 100 mg daily from day 10 for Patient 1; 200 mg daily for the whole treatment period for Patient 2). Fluconazole bile and plasma Cmin (Table 1) were 9.04 and 17.81 mg/L, respectively at therapy day 9 for Patient 1, and 6.29 and 12.61 mg/L at therapy day 5 for Patient 2. Patient 3 (60–70 years, 60–70 kg and serum creatinine 1.7 mg/dL) developed Candida peritonitis at day 62 post-transplant, after a history of recurrent, refractory ascites. Cultures from ascites yielded C. albicans susceptible to fluconazole (MIC 0.25 mg/L; Sensitire YeastOne colorimetric MIC procedure). Intravenous fluconazole was started with a 400 mg loading dose followed by a maintenance dose of 150 mg daily, then reduced to 100 mg daily from day 8. Fluconazole Cmin in ascites and plasma at therapy day 5 was 9.60 and 11.30 mg/L, respectively (Table 2). The fluconazole bile-to-plasma ratios of Cmin in the two LTx patients with cholangitis (0.50 and 0.51) were lower than previously observed in a non-LTx patient with Candida cholecystitis (around 1.2 at therapy day 5 by visual inspection).8 Conversely, the ascites-to-plasma ratio of Cmin in the LTx patient with peritonitis (0.85) was similar to that observed in a non-LTx cirrhotic patient with Candida peritonitis (0.81 at 3 h post-dose at therapy day 5).9 Interestingly, 14 days of fluconazole treatment with maintenance of plasma Cmin at around 15 mg/L resulted in clinical resolution of intra-abdominal candidiasis in all three LTx patients with no evidence of recurrence at 30 days of follow-up. It should be noticed that, thanks to TDM, in these particular patients successful treatment was based on doses of fluconazole much lower (100 – 200 mg/day) than those usually administered for systemic infections (400–800 mg/day).6 Previous studies showed that the AUC/MIC ratio is the pharmacodynamic parameter that best correlates with fluconazole efficacy,5,10 and the recent
2585
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on April 28, 2015
8 CDC. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep 2012; 61: 839–42.
JAC
