Invasive aspergillosis (IA) is one of the major causes of morbidity and mortality in severely immunocompromised patients. Despite the existence of antifungal treatment IA mortality rate remains extremely high and may reach up to 80%. Previous studies have suggested important role of platelets in antifungal host defence. In vitro data show that platelets are able to attenuate germination, hyphal elongation and viability of Aspergillus fumigatus. Interaction of platelets with Aspergillus fumigatus induces differential expressions of fungal genes associated with stress response regulation, cellular transport and metabolism. A new class of antifungals, echinocandins (caspofungin, micafungin and anidulafungin), have entered the market. Anidulafungin displays strong antifungal activity against Candida and Aspergillus species and has very few side effects due to its specific inhibiting effect on the fungal cell wall synthesis. Anidulafungin is currently licensed for the treatment of adult patients with invasive candidiasis. Clinical significance of anidulafungin for IA treatment has to be further evaluated. Recently published studies have shown that efficiency of antifungal substances can be enhanced when combined with platelets. In this review we discuss the literature on the potential combined effect of platelets and anidulafungin against Aspergillus fumigatus infections.
Abstract Purpose Wound infections caused by Candida are life-threatening and difficult to treat. Echinocandins are highly effective against Candida species and recommended for treatment of invasive candidiasis. As penetration of echinocandins into wounds is largely unknown, we measured the concentrations of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) in wound secretion (WS) and in plasma of critically ill patients. Methods We included critically ill adults with an indwelling wound drainage or undergoing vacuum-assisted closure therapy, who were treated with an echinocandin for suspected or proven invasive fungal infection. Concentrations were measured by liquid chromatography with UV (AFG and MFG) or tandem mass spectrometry detection (CAS). Results Twenty-one patients were enrolled. From eight patients, serial WS samples and simultaneous plasma samples were obtained within a dosage interval. AFG concentrations in WS amounted to < 0.025–2.25 mg/L, MFG concentrations were 0.025–2.53 mg/L, and CAS achieved concentrations of 0.18–4.04 mg/L. Concentrations in WS were significantly lower than the simultaneous plasma concentrations and below the MIC values of some relevant pathogens. Conclusion Echinocandin penetration into WS displays a high inter-individual variability. In WS of some of the patients, concentrations may be sub-therapeutic. However, the relevance of sub-therapeutic concentrations is unknown as no correlation has been established between concentration data and clinical outcome. Nevertheless, in the absence of clinical outcome studies, our data do not support the use of echinocandins at standard doses for the treatment of fungal wound infections, but underline the pivotal role of surgical debridement.
Systemic fungal infections are a major threaten for immunocompromised patients. Beside the antimycotic spectrum, the pharmacokinetic properties of an antifungal drug are crucial for its clinical efficacy. Since patients with systemic mycoses frequently present with a significant co-morbidity, pharmacokinetics under special conditions such as renal insufficiency, renal replacement therapy or impaired liver function have to be considered. Amphotericin B is eliminated unchanged by the liver and the kidney. Its plasma protein binding accounts for 95 to 99 percent. Conventional amphotericin B deoxycholate has a remarkable infusion related and renal toxicity. Therefore, lipid formulations have been developed. By now, three lipid formulations are therapeutically used: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex. Striking differences in their plasma pharmacokinetics have been found. These differences can be attributed to the diverse disposition of the lipid moieties, while liberated amphotericin B displays a pharmacokinetic behavior which is independent from the lipid-formulation applied. The highest amphotericin B tissue concentrations have been found in the liver and in the spleen, followed by lung, kidney and heart. Concentrations in brain tissue are very low. Flucytosine has no relevant protein binding and is eliminated by glomerular filtration. Fluconazole, itraconazole, voriconazole, posaconazole and ravuconazole are triazoles, used for treatment of systemic fungal infections. Significant drug interactions have to be considered during therapy with triazoles, particularly in patients dependent on immunosuppression. These interactions are caused by the metabolism of triazoles in the liver where the cytochrome P450 (CYP) system is involved at a different extend as well as by their mechanisms of action. Triazoles display a favorable tissue distribution with high penetration into the central nervous system. Echinocandins such as caspofungin and micafungin are rapidly taken up by peripheral tissues, particularly by the liver. In the first 24 hours this uptake appears to be the main route of elimination from plasma. Enzymatic degradation takes place, but is independent of CYP. Thus, drug interactions are a minor problem during echinocandin treatment. The highest tissue levels of caspofungin and micafungin have been measured in the liver. Moderate concentrations are achieved in lung, spleen and kidney. Penetration into the brain is relatively poor. Keywords: Amphotericin B, triazoles, echinocandins, drug interactions, elimination, tissue penetration,, site pharma-cokinetics
Invasive fungal diseases (IFD) are an important cause of morbidity and mortality in immunocompromised patients, and early diagnosis and management are a challenge. We evaluated the clinical utility of computed tomography (CT)-guided percutaneous lung biopsies in diagnosing IFD. Between 2003 and 2014, we analyzed 2671 CT-guided lung biopsies, from which 157 were IFD associated; we aimed to determine microbiological-based diagnostic accuracy of calcofluor white staining (CFWS), culture, Aspergillus antigen detection (GM), broad-range fungal PCR, and Aspergillus PCR per sample. 127 (81%) specimens were microscopically positive for any fungal elements, 30 (19%) negative. Aspergillus and non-Aspergillus like hyphae were obtained in 85 (67%) and 42 (33%) specimens, respectively. CFWS positivity was defined as proof of infection. Sensitivity, specificity, and positive (PPV) and negative predictive (NPV) values for CT scan were 100, 44, 80, and 100%, for Aspergillus PCR 89, 58, 88, and 58%, for broad-range fungal PCR 90, 83, 95, and 90%, and for GM 94, 83, 95, and 90%. The most common CT features were patchy opacifications with central necrosis (78%) or cavern defects (50%), less common were air bronchograms (39%) or ground glass halos (39%), and all other features were rare. The overall pneumothorax rate subsequent to biopsy was 19%, but in only 2% of all cases the placement of a chest tube was indicated. One case of fatal air embolism occurred. CT-guided lung biopsies have high diagnostic accuracy in terms of microscopic examination, and complication rates are low. Molecular-based and antigen tests applied on fungal hyphae-positive specimens showed comparable results.
Invazivni mykoticka onemocněni patři k zavažným život ohrožujicim stavům imunokompromitovaných pacientů. Zavedeni antimykotika
Amphotericinu B (AmB), respektive jeho různých lekových forem, do klinicke praxe vedlo k výraznemu zlepseni lecebných výsledků
a ke sniženi mortality imunokompromitovaných pacientů s prokazanou nebo předpokladanou invazivni mykozou (1). Limitaci zůstava
jeho toxicita – akutni a opožděna nefrotoxicita a akutni s infuzi spojena nežadouci reakce (Infusion – related reaction – IRR). Nefrotoxicita
je nyni ovlivnitelna volbou vhodne lekove formy AmB a adekvatni podpůrnou peci, předevsim hyperhydrataci (2). IRR v podobě pyrexie,
třesavky, zimnice vsak zatim zcela odstranitelna neni a ani zavedeni premedikace s výjimkou kortikoidů přilis neovlivnilo incidenci
IRR (3). Vzhledem k nejasne patogenezi IRR a jen ojedinělým systematickým prospektivnim studiim, vedly snahy o minimalizaci IRR
k prospektivni studii u pediatrických onkologických pacientů s indikovaným podanim AmB. Flowcytometricke stanoveni subpopulaci
lymfocytů a stanoveni hladin interleukinů v korelaci s plazmatickými hladinami AmB, s klinickou incidenci IRR, lekovou formou AmB
a s typem premedikace svědci pro intimni vztah změny v množstvi paměťových efektorových Th lymfocytů a v interleukinovem spektru
a incidenci IRR.
Tissue concentrations of caspofungin were determined in nine clinically relevant tissues taken during routine autopsy of 20 patients who had died during caspofungin treatment or within 23 days of cessation. The highest levels were achieved in liver, with concentrations ranging from ≤0.50 to 91.5 µg/g (0.60 µg/g 21 days after the last administration), followed by spleen (<0.25-46.3 µg/g), kidney (<0.25-33.6 µg/g) and lung (<0.25-31.0 µg/g). Intermediate concentrations were found in pancreas, skeletal muscle, thyroid and myocardium. The lowest concentrations were found in brain; caspofungin was only detectable in six of 17 samples. Caspofungin concentrations exceeded the minimum inhibitory concentration values of pathogenic Candida spp. in most of the tissue samples taken from patients who had died during treatment, except in brain samples. These findings warrant clinical outcome studies to establish the optimal treatment for deep-seated candidiasis, and support the current recommendations against echinocandins for treatment of fungal meningoencephalitis.
