Antibiotic treatment of systemic fungal infections

Current Anaesthesia and Critical Care (1997) 8, 180-183

© 1997 Pearson Professional Ltd

Medicine

Antibiotic treatment of systemic fungal infections

J. P. Burnie

Systemic fungal infections remain a major cause of mortality in the intensive care unit. This paper summarizes the clinical syndromes and reports on recent advances in the oral azole drugs, fluconazole and itraconazole, and systemic liposomal-based variants of amphotericin B, which may now be used in therapy. Individual drugs are reviewed and then the therapy of disseminated candidiasis and invasive aspergillosis is discussed. Emphasis is also placed on preventive measures, which include: adequate handwashing; wellmaintained air ventilation; and the removal of potential fornites, such as contaminated bottles, cups, toothbrushes, cutravenous lines and feeds, and poorly-maintained microwaves.

Introduction Systemic fungal diseases remain a major cause of mortality in the intensive care unit (ITU). This is owing to the selective pressure of broad-spectrum antibiotics, the prolonged stay of patients in the ITU, the difficulty in diagnosing the infection and the low efficacy of the agents used in therapy. The major pathogens can be subdivided into yeasts and moulds. The former are usually endogenous in origin, but can cause outbreaks where, predominantly, hand transmission has been implicated, ~the latter is associated with building work and spread by the air and on occasion on food. 2 It is, thus, essential to eliminate cross infection by vigorous monitoring for clusters of the same fungus and employing adequate hand hygiene involving wearing gloves, where applicable, washing hands in Hibisol or Povidone-Iodine rather than soap and removing fomites. These include inadequately maintained air-ventilation units, high-risk foodstuffs e.g. pepper (Aspergillus niger), contaminated bottles (neonatal units, Candida spp), cups, toothbrushes, intravenous lines and feeds (Candida spp especially Candida parapsilosis), and poorly maintained microwaves (Aspergillus niger). When major Professor James P. Burnie, Medical Microbiology, 2nd Floor, Clinical Sciences Building, Oxford Road, Manchester Royal Infirmary, Manchester M13 9WL, UK

building work is being undertaken then the possibility of hospital acquired aspergillosis should be borne in mind and an attempt made to minimize disruption. In order to start treatment it is necessary to make the diagnosis. The two most common systemic fungal infections are invasive candidiasis and invasive aspergillosis. The typical presentation of invasive candidiasis is nonspecific with a temperature, shock and lack of response to broad-spectrum antibiotics. A history of previous gastrointestinal surgery, especially operations involving impairment of the acid barrier in the stomach, is helpful. The typical rash ('acne'-like lesions over the abdomen and lower chest) and endophthalmitis ('white fluffy exudates') are rare. Blood cultures are only positive in about 50% of cases subsequently diagnosed at autopsy. Positive cultures helpful in making the diagnosis include: urine, especially in the absence of a urinary catheter; chest drain, especially after upper gastrointestinal surgery; intravenous line; and faeces, where Candida spp is the dominant isolate. The species is important, as the more virulent include Candida albicans, Candida tropicaIis, Candida krusei and the less virulent C. parapsilosis and Torulopsis glabrata. C. albicans, C. tropicalis and C. parapsilosis are sensitive to amphotericin B, whilst C. krusei and T. glabrata are resistant to fluconazole and often occur in patients where this drug has been used as prophylaxis. The level of fluconazole resistance 180

ANTIBIOTIC TREATMENT OF SYSTEMIC FUNGAL INFECTIONS

in C. albicans is controversial and it has been reported in HIV positive patients as running at 5-10%. Serological diagnosis is difficult with antibody detection regarded as prognostic rather than diagnostic. Antigen detection has achieved a low sensitivity with latex agglutination detecting a cytoplasmic antigen, and the specific detection of enolase and candidal heat-shock protein 90 all being advocated. The detection and subsequent quantification of candidal DNA from ribosomal sequences by the polymerase chain reaction (PCR) is now emerging as a way forward. 3 Invasive aspergillosis is primarily a chest disease that disseminates to other organs such as the brain. Paradoxically, in a neutropenic patient the chest X-ray can appear normal despite widespread disease, and it can be missed on bronchoscopy. CT scanning is superior at demonstrating the discrete lesions, but does not provide histological or morphological proof. Sputum production may not occur in up to one third of patients, and the isolation of Aspergillus spp from a single sputum does not mean that it is causing disease. Repeat isolation of the same species is much more significant, whilst the isolation of the mould from a blood culture is almost always a contaminant, with the exception of the rare patient with fungal endocarditis. Serological diagnosis is insensitive, and the detection of fungal DNA by PCR has been shown to work with bronchial aspirates, but there is a high rate of false positives. Therapy will be discussed focusing on the key agents first and then suggesting protocols for the individual diseases.

Oral azole drugs The azoles are classified as imidazoles (miconazole and ketoconazole) or triazoles (itraconazole and fluconazole) according to whether they contain two or three nitrogen atoms. They inhibit ergosterol synthesis through an interaction with C-14 ~ demethylase, which is necessary for the conversion of lanosterol to ergosterol. Itraconazole is available only as an oral preparation. Owing to its kinetics, a loading dose of 200 mg of itraconazole 3 times daily for 3 days is recommended in patients with serious infection.4 Fluconazole is available in both oral and intravenous formulations. Itraconazole is extensively metabolized in the liver and excreted almost exclusively in the faeces and urine. Fluconazole is minimally metabolized and approximately 80% of an administered dose is excreted unchanged in the urine. The dose should be reduced in patients where the glomerular filtration rate is below 50 ml/min. Fluconazole is effectively removed during haemodialysis, and to a lesser extent during peritoneal dialysis. The spectrum of activity is such that itraconazole is perceived to be more active against the Aspergillus spp whereas fluconazole is considered to be the better agent against yeasts, notably C. albicans and Cryptococcus neoformans. Cases of invasive aspergillosis have devel-

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oped on fluconazole prophylaxis, so that the dominant type of fungal infection in a unit should be considered when either of these agents is used as prophylaxis. Side effects include rare cases of hepatitis, nausea and vomiting. The agents can interfere with the activity of hepatic microsomal processes leading to clinically important increases in the plasma concentrations of drugs such as cyclosporine, digoxin, phenytoin, tolbumide, warfarin etc.4

5-fluorocytosine 5-fluorocytosine (5-FC) is the fluorine analogue of cytosine. It enters the cell, becomes deaminated to 5fluorouracil, is phosphorylated and is then incorporated into RNA. It is perceived as solely active against yeasts but has a scientifically proven synergy with amphotericin B in the treatment of cryptococcal meningitis. In disseminated candidiasis there is the problem of resistance prior to therapy and the development of high level resistance during therapy. Thus, the drug is never, with the exception of a candidal urinary tract infection, used as monotherapy; it is combined with amphotericin B. Toxicity is mostly haematological, ranging from mild anaemia to marrow aplasia where thrombocytopenia can be a dominant manifestation. This may be idiosyncratic but normally occurs when serum drug levels are greater than 100 mg/ml. This necessitates close monitoring as the drug is cleared in the urine so that nephrotoxicity, as a result of the coadministration of amphotericin B, is likely to lead to 5-FC retention. The usual dose is 50 to 150 mg/kg/day divided into four doses, with the current trend being to use a lower rather than higher dose. 5

Amphotericin B Conventional amphotericin B is regarded as the gold standard of systemic antifungal therapy. Its use is hampered by the high rate of side effects during administration, e.g. chills, fever, myalgia, thrombophlebitis or subsequently where nephrotoxicity, hypokalaemia, hypomagnesaemia, anaemia and thrombocytopenia (more rare) occur. Recently four newer formulations have become available. These include AmBisome where the drug is incorporated into a bilayer of small unilamellar liposomes (45-80 nm) composed of hydrogenated soy phosphatidylcholine, distearoyl phosphatidylglycerol and cholesterol. 6 Efficacy has been demonstrated in 133 neutropenic episodes in 116 patients with proven or probable invasive fungal infections, where the drug was used because conventional amphotericin B had failed or led to nephrotoxicity.7 Adverse effects were infrequent and no significant renal impairment resulted. Thirteen out of 17 patients with confirmed invasive aspergillosis responded to AmBisome. There has also been evidence of activity in a placebo controlled antifungal prophylaxis study.8 The second formulation is amphotericin-B lipid

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CURRENT ANAESTHESIA AND CRITICAL CARE

complex, Abelcet (ABLC) with a 33% concentration of amphotericin B in microparticulate polymorphic sheets and ribbons. Limited toxicity with prolonged therapy using high doses was reported in six patients with a variety of deep-seated fungal infections. 9 In a further study, commented on by Graybill, 1° 231 patients with invasive candidiasis were randomly assigned in a 2:1 ratio to receive ABLC (5 mg/kg/day) or amphotericin B (0.6 to 1.0 mg/kg/day). The two groups had similar predisposing factors. Of the 194 patients evaluated, 65% of ABLC recipients and 61% of amphotericin B recipients responded to their respective d r u g s . 11 The third formulation is amphotericin-B colloidal dispersion (ABCD), Amphocil. This is a non-liposomal lipid formulation of small disc-shaped particles. In an open trial, ABCD at doses as high as 6 mg/kg/day was administered to 168 patients with documented or presumed systemic mycoses, who had responded incompletely to at least 7 treatment days of conventional amphotericin B. Complete clinical response or improvement was noted in 48 patients after a mean treatment duration of 18.5 days. There was little renal toxicity and hypokalaemia occurred in 5%. 12 The fourth formulations are anecdotal reports of the use of amphotericin-B with the fat emulsions used for parenteral nutrition. 1°'13 In one study, 13 out of 14 episodes of candidaemia in neutropenic patients treated with amphotericin-B intralipid emulsion (mean dose 1.18 mg/kg/day) showed a clinical response.14 In summary, a lipid formulation of amphotericin-B should be considered in the management of an invasive fungal infection where the patient has renal insufficiency. 13 There is still debate as to which formulation is best, the appropriate dose and length of therapy and whether the treatment is worth the increased cost. 1°'13

Candidal endophthalmitis This is a sight-threatening ocular infection that occurs as a complication of candidaemia. It often occurs after previous candidal colonization of a central venous line where it is associated with hyperalimentation and is a complication of C. albicans sepsis during pregnancy. A similar picture can occur in drug addicts. Conventional amphotericin-B therapy has now given way to fluconazole, 17 which is tolerated and effective at doses of up to 800 mg/day.

Candidal endocarditis This has been reported following central- and intravenousline colonization, on prosthetic valves and in premature infants. It is associated with C. parapsilosis colonization of lines during hyperalimentation. This is important, as this yeast is of low virulence and infection is self limiting if the line is removed before the heart becomes infected. Treatment of established infection should be aggressive with pre-operative amphotericin-B; radical resection of all infected tissue; cardiac reconstruction, using biological tissue when possible; and prolonged oral-suppressive antifungal therapyJ 8

Candidal-line infections Intravascular catheters are a high risk factor in the development of candidaemia, and failure to remove catheters has led to prolonged fungaemia, treatment failure and increased mortality. Catheter exchange is an essential component in the treatment of patients with candidaemia. 19

Disseminated candidiasis

Clinical conditions Candida[ urinary-tract infection Suggested treatments have included amphoteriein-B bladder washouts, oral fluconazole, oral 5-FC and systemic amphotericin-B. One study compared amphotericin bladder irrigation (50mg/l over 24h) with fluconazole (200 rag/day for 7 days) and obtained identical results, with the exception of the appearance of T. glabrata infection in the fluconazole treated group. 15 The spectrum of infection ranges from cystitis to ascending renal candidiasis, and from ureteropelvic fungus balls to disseminated disease with renal involvement. Nassoura et al 199316 examined 27 patients in the surgical intensive care unit who had candiduria (>100 000 colonies/m1) treated with amphotericin-B bladder irrigation. These patients had a dissemination incidence of 63% and a septic mortality rate of 33%. They then prospectively treated these patients with fluconazole (400 mg loading dose and 200 mg/day) and demonstrated a 0% incidence of dissemination and a significant reduction in septic mortality to 5%.

Amphotericin-B is considered the gold-standard therapy. Common practice is to administer a I mg test dose to observe for hypersensitivity, but this has recently become less fashionable. The target dosage and length of treatment, based on data by Solomkin et al 1982, 20 is 0.5 mg/kg/day for 12-14 days, although higher dosages have been used. 5-FC can be added if there is evidence of central nervous system or renal involvement and it is usually contraindicated if the patient is neutropenic or thrombocytopenic. The role of the liposomal formulations is controversial with cost being a dominant factor. There are no clear data supporting the use of any individual formulation, but the evidence that they lack the nephrotoxicity of convential amphotericin-B is compelling. Thus, they are the drugs of choice in patients with renal failure. The dosage is still controversial with a range of from 1 mg/kg/day to 5 mg/kg/day being suggested. Alternatively, in non-neutropenic patients with a candidaema, a dose of 400 rag/day of fluconazole for at least 14 days after the last positive blood culture was shown to be equivalent to 0.5-0.6 mg/kg/day of amphotericin-B.21

ANTIBIOTIC TREATMENT OF SYSTEMIC FUNGAL INFECTIONS

Invasive aspergillosis Two drugs are useful for therapy, amphotericin-B and itraconazole. Surgical resection of localized chest lesions demonstrated by CT scanning should also be considered. Conventional amphotericin-B is given at a dose of 1 mg/kg/day and this is continued up to an arbitrary total dose of 1-2 g.22 An alternate is one of the liposomal preparations of arnphotericin-B. Doses advocated are higher than those for disseminated candidiasis at 4--5 mg/kg/day. 7'22 The alternative is itraconazole. In a large open multicentre study, performed by the Mycoses Study Group in the USA, 41% of patients with invasive aspergillosis showed a complete or partial response to itraconazole (600 rag/day for 4 days followed by a minimum of 400rag/day). 23 Higher doses of up to 800mg/day have been used successfully in cases of cerebral aspcrgillosis) 4 However, the drug can only be given orally as yet, which limits its value. Anecdotal reports of response to 5-FC or rifampicin have also been described. 22

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Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. Transplantation 1995; 59: 45-50. 9. Kline S, Larsen T A, Fieber Let al. Limited toxicity of prolonged therapy with high doses of amphoteriein B lipid complex. Clin Infect Dis 1995; 21:1154-I 158. 10 Graybill J R. Lipid formulations for amphotericin B: Does the emperor need new clothes? Annals Int Med 1996; 124:921-923 11 Anaissie E J, White M, Uzun Oet al. Amphotericin B lipid complex (ABLC) versus amphotericin B (AMB) for the treatment of hematogenous invasive candidiasis: a prospective randomized, multicentre trial [Abstract]. In: Thirty-fifth Interscience Conference on antimicrobial agents and chemotherapy. San Francisco, CA, 1995. 12. Oppenheim B A, Herbrecht R, Shimon K. The safety and efficacy of amphotericin B colloidal dispersion in the treatment of invasive mycoses. Clin Infect Dis 1995; 21:1145-1153. 13. Hiemenz J W, Walsh T J. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 1996:22 Suppl: S 133-S 144. 14. Caillot D, Casasnovas O, Solary E et al. Efficacy and tolerance of an amphotericin B lipid (intralipid) emulsion on the treatment of candidaemia in neutropenic patients. J Antimicro Chem 1993: 31: 161-169. 15. Fan-Havard P, O'Donovan C, Smith S M, Oh J, Bamberger M. Oral fluconazole versus amphotericin B bladder irrigation for treatment of candidal funguria. Clin Infect Dis 1995; 21(4): 960-965. 16. Nassoura Z, Ivatury R R, Simon R Jet al. Candiduria as an early marker of disseminated infection in critically ill surgical patients the role of fluconazole therapy. J Trauma 1993; 35: 290-295. 17. Akler M E, Vellend H, McNeely D M, Walmsley S L, Gold W L. Use of fluconazole in the treatment of candidal endophthalmitis. Clin Infect Dis 1995; 20(3): 657-664. 18. Muehrcke D D, Lyre B W, Cosgrove D M. Surgical and long-term antifnngal therapy for fungal prosthetic valve endocarditis. Ann Thorac Snrg •995; 60(3): 538-543. 19. Rex J H, Bennett J E, Sugar A M, Pappas P G, Serody J, Edwards J E, Washburn R G. Intravascular catheter exchange and duration of candidemia. Clin Infect Dis 1995; 21: 994--996. 20. Solomkin J S, Flohr A, Simmons R L. Candida infections in surgical patients. Dose requirements and toxicity of amphotericin B. Ann Surg 1982; 195(2): 177-185. 21 Rex J H, Bennett J E, Sugar A M, Pappas P G, van der Horst C M, Edwards J E, Washburn R G, Scheld W Met al. A randomized trial comparing fluconazole with amphotericin treatment of candidemia in patients without neutropen. New Engl J Med 1994; 331: 1325-1330. 22. Denning D W. Treatment of invasive aspergillosis. J Infect 1994; 28 Suppl 1: 25-33. 23. Denning D W, Lee J Y, Hostetler J Set al. NIAID Mycoses Study Group multicentre trial of oral itraconazole therapy for invasive aspergillosis. American J Med 1994; 97: 135-144. 24. S~inchezC, Manri E, Dalmau D, Quintana S, Aparicio A, Garan J. Treatment of cerebral aspergillosis with itraconazole: do high doses improve the prognosis? Clin Infect Dis 1995; 21: 1485-1487.