Combination antifungal treatment of

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Jun 16, 2009 - Taylor A, Patterson TF, Denning DW,. Walsh TJ (2004) Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients ...
Intensive Care Med (2009) 35:1641–1643 DOI 10.1007/s00134-009-1546-9

CA SE DISCUSSION

Goldman class I discrepancy (a missed major diagnosis with major impact on patient management and survival) [3]. The epidemiology of IA indicates an increasing number of infections in immunosuppressed patients/individuals undergoing transplantation of bone marrow, hematopoietic stem cells, or organ transplantations, and those receiving intensive chemotherCombination antifungal apy or other immunosuppressive treatment of treatments. A broad group of patients pseudomembranous who are admitted to ICU also have some form of immunosupppression tracheobronchial invasive and may be susceptible to invasive aspergillosis: a case report mould infections. For various reasons, figures about the true incidence Received: 18 February 2009 of IA in ICU are difficult to generate. Accepted: 5 April 2009 Published online: 16 June 2009 The most important reason is the Ó Springer-Verlag 2009 difficulty encountered in making a definite diagnosis of IA (lack of sensitivity and specificity with regard to culture and radiology) [4]. Recently, galactomannan (GM) in bronchoIntroduction alveolar lavage (BAL) fluid appears to be a promising tool for early Invasive aspergillosis (IA) is diagnosis in non-neutropenic critiincreasingly recognized in the inten- cally ill patients and has been sive care unit (ICU), and new risk associated in proven cases with senfactors associated with respiratory sitivity and specificity of 88 and 87%, colonization or infection by Asperrespectively [5]. gillus spp. include steroid treatment Pseudomembranous and obstrucand chronic lung obstructive disease tive Aspergillus tracheobronchitis are [1, 2]. In a review of 289 autopsies in still considered to have a fatal outthe ICU, IA was the leading cause of come and have been reported in a Francesco G. De Rosa Pierpaolo Terragni Daniela Pasero Anna C. Trompeo Rosario Urbino Anna Barbui Giovanni Di Perri V. Marco Ranieri

Fig. 1 CT scan of the lungs showing bilateral alveolar and peribronchial lesions compatible with invasive aspergillosis. Bilateral pleural effusions are also present

wide variety of patients [6]. There has been only one report in a patient with diabetes which was treated by deoxycholate amphotericin B (AmB) and subsequent addition of oral itraconazole [7]. In this paper, we report a pseudomembranous and obstructive tracheobronchitis in a diabetic patient successfully treated with caspofungin and AmB. Case report A 57-year-old diabetic, HIV-negative, Caucasian man was admitted to the Emergency Department of the S. Giovanni Battista Hospital for diabetic ketoacidosis. After 2 days, the patient was hemodynamically unstable with an APACHE II score of 24 and was admitted to the ICU with acute respiratory failure and bilateral pneumonia. Mechanical ventilation was started and antibiotic treatment was administered with meropenem, ciprofloxacin and vancomycin. On the fourth day there was no clinical response, the WBC count was 19,700/ mm3 with neutrophilia and left shift. A CT scan showed multiple small bilateral nodules together with signs of interstitial disease (Fig. 1), and diffuse bilateral purulent secretions were seen upon bronchoscopy. A BAL was performed and only fungal

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24 CI AmB-d CAS

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Fig. 2 A summary is given of the main data regarding treatment (VOR voriconazole, CI AmB continuous infusion of Amphotericin B, CAS caspofungin), results of cultures on BAL (?, positive; -, negative) and galactomannan index (GM Index by Platelia Aspergillus Biorad assay; squares BAL, rhombus serum) over the several weeks of ICU admission of the reported patient

hyphae were documented by microscopic examination. Since serum GM was positive (4.32), intravenous voriconazole was started at standard dosage and drotrecogin alpha was given for septic shock. Clinical conditions did not improve and at day 7 serum GM was still positive (1.62). At day 11, serum ALT and AST were 516 and 1361 IU/mL, respectively, and voriconazole was stopped. Respiratory parameters worsened (PaO2/FiO2 \ 200) with episodes of bronchospasm. At day 14, a bronchoscopy demonstrated tracheobronchial pseudomembranes almost totally occluding the left main bronchus. The microscopic examination of the bronchial exudate and the transbronchial biopsy showed septate hyphae branching at 45° consistent with Aspergillus. The BAL analysis demonstrated elevated levels (16.3) of GM (Fig. 2) with positive results of fungal cultures. Serum antiAspergillus IgE were negative. Antifungal treatment was changed to AmB (continuous infusion of 1.5 mg/ Kg/day, based on normal renal function) and caspofungin (70 mg on day 1, and 50 mg by the second day). Antibiotic treatment was stopped at day 15 and antifungal combination

treatment was continued up to day 35 without any side-effect. On day 60, mechanical ventilation and intravenous treatment were stopped and oral voriconazole was reinstituted without signs of liver toxicity. The patient was discharged alive from the hospital. Galactomannan was measured in all BALs performed during the ICU stay and the findings are illustrated in Fig. 2 together with a summary of the results of cultural examinations for A. fumigatus.

Discussion To our knowledge, this is the first report of clinical success with antifungal combination treatment of a pseudomembranous and obstructive form of IA in a diabetic patient. In general, voriconazole is considered the first-line antifungal in IA [8] and in tracheobronchial aspergillosis, with an evidence of B-II in the latest IDSA guidelines [9]. Caspofungin is only approved for salvage treatment [10]. AmB is commonly associated with nephrotoxicity which seems to be reduced with continuous

infusion, also without lack of efficacy in antifungal prophylaxis when including high-risk hematology patients [11], although the administration of AmB should be optimised with once daily administration owing to the concentration-dependent pharmacodynamics [12]. The pharmacodynamics of AmB are not completely understood. In an in vitro study against Cryptococci, a rapid fungicidal activity was observed at concentrations above the minimum inhibitory concentrations (MIC). However, after 24 h of incubation, the same fungicidal activity was observed with concentrations well above the MIC and around the MIC [13]. These data may suggest that concentrations equal to the MIC are effective in vivo, where drug diffusion at the infection site is more important than plasma concentrations. Combination treatment with AmB and caspofungin was effective in our patient with pseudomembranous and obstructive form of IA. This choice of drugs is attractive, since both have very different targets: AmB has its activity against the fungal cell membrane, whereas the target of caspofungin is the beta 1,3-D glucan of the cell wall [14]. The diagnosis of pseudomembranous Aspergillus tracheobronchitis was made on the typical findings by bronchoscopy and probably deserves different criteria from those proposed by Vandewoude [4]. The diagnosis is definite as evidenced by histology of pseudomembranes and positive results of cultures. The BAL GM levels decreased with effective treatment that started with voriconazole and continued with combination treatment which was chosen because of the different mechanisms of action of the two drugs, even if combination therapy lacks sufficient evidence so far, with the possible exceptions of breakthrough infections or refractory disease [15]. In conclusion, this is the first report of a successful treatment with caspofungin and continuously

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infused AmB of an almost uniformly fatal disease.

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7. Chang SM, Kuo HT, Lin FJ, Tzen CY, Sheu CY (2005) Pseudomembranous tracheobronchitis caused by Aspergillus in immunocompromized patients. Scand J Infect Dis 37:937–942 8. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B (2002) Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347:408–415 9. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard JR, Patterson TF (2008) Treatment of aspergillosis: clinical practice guidelines of the infectious diseases society of America. Clin Infect Dis 46:327–360 10. Maertens J, Raad I, Petrikkos G, Borgaerts M, Selleslag D, Petersen FB, Sable CA, Kartsonis NA, Ngai A, Taylor A, Patterson TF, Denning DW, Walsh TJ (2004) Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 39:1563–1571 11. Peleg AY, Woods ML (2004) Continuous and 4 h infusion of amphotericin B: a comparative study involving high-risk haematology patients. J Antimicrobl Chem 54:803– 808 12. Andes D, Safdar N, Marchillo K, Conklin R (2006) Pharmacokineticpharmacodynamic comparison of amphotericin B (AMB) and two lipidassociated AMB preparations liposomal AMB and AMB lipid complex in murine candidiasis models. Antimicrob Ag Chemother 50:674–684

13. Klepser ME, Wolfe EJ, Pfaller MA (1998) Antifungal pharmacidynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans. J Antimicrob Chemother 41:397–401 14. Sionov E, Mendlovic S, Segal E (2006) Efficacy of amphotericin B or amphotericin-intralipid in combination with caspofungin against experimental aspergillosis. J Infect 53:131–139 15. Trof RJ, Beishuizen A, bets-Ossenkopp YJ, Girbes ARJ, Groeneveld ABJ (2007) Management of invasive pulmonary aspergillosis in nonneutropenic critically ill patients. Intensive Care Med 33:1694–1703 F. G. De Rosa  G. D. Perri Dipartimento di Discipline MedicoChirurgiche, Sezione di Malattie Infettive, Ospedale Amedeo di Savoia, Corso Svizzera 164, 10149 Torino, Italy P. Terragni  D. Pasero  A. C. Trompeo  R. Urbino  V. Marco Ranieri Dipartimento di Anestesia, Ospedale S.Giovanni Battista-Molinette, Torino, Italy A. Barbui Laboratorio di Microbiologia, Universita` di Torino, Ospedale S. Giovanni Battista-Molinette, Torino, Italy F. G. De Rosa ()) Clinica Delle Malattie Infettive, Ospedale Amedeo di Savoia, Corso Svizzera 164, 10149 Torino, Italy e-mail: [email protected] Tel.: ?39-011-4393926 Fax: ?39-011-4393882