- Email: [email protected]
The role of chemoprophylaxis in the prevention of airborne infection by fungal pathogens
Journal of Hospital Infection (1991) 18 (Supplement
A), 460-465
The role of chemoprophylaxis in the prevention airborne infection by fungal pathogens
of
R. J. Hay Department
of Dermatology,
Guys
Hospital,
London
SE1
9RT,
UK
Summary: The main approach to prevention of infection following airborne transmission of pathogenic fungi such as Aspergillus species has been environmental. However, there are a number of potentially effective methods of prophylaxis using antifungal drugs. Those described previously include itraconazole or amphotericin B given by the intranasal or intrapulmonary route after nebulization. Another possibility for investigation in the future is enilconazole which is highly active against aspergilli after inhalation in animals and which has been used in the treatment of aspergillosis in poultry. Keywords: Aspergillus;
Candida; antifungal
drugs;
chemoprophylaxis.
Introduction
The use of drugs to anticipate and thereby prevent the invasion of fungi in immunocompromised patients has long formed part of the strategy of the management of this group, but has also been the subject of scepticism and controversy. While generally the target organism is Candidu al&cans, whose presumed principal site of entry is the gastrointestinal tract, the evaluation of the use of regimens aimed at reducing the risk of invasion is difficult to Many studies have contained too few patients to perform and interpret.’ form a valid view of the success of the approach and the diagnosis of invasive candidosis in the group at most risk, the neutropenic patient, is itself difficult because of the lack of clinical signs and symptoms and the inaccuracy of present methods of laboratory diagnosis. Where, in such studies, proven invasive fungal infections have occurred the numbers have usually been too small to compare with any degree of statistical accuracy. Chemoprophylaxis aimed at other fungi has not generally been the subject of much research even though there are many reasons why this should be a valid approach. The purpose of this paper is to explore the potential role of protection of patients at risk from airborne infection due to other fungi, particularly Aspergillus spp., using drugs. The
antifungal
agents
The selection of drugs for chemoprophylaxis that are effective in a wider range of fungal infections is clearly important. There are three major 0195S6701/91/06A460+06
$03.00/O
0 1991 The Hospital
460
Infection
Society
Chemoprophylaxis
of fungal
infection
461
families of antifungal drugs: the polyenes, the azoles and the allylamines. In addition there is a miscellaneous group of compounds such as flucytosine and griseofulvin which do not belong to a single family of drugs. There are also new groups of antifungals, under development such as the morpholines* (amorolfine) and the echinocandins such as cilofungin.3 However, the principal antifungals used against the systemic mycoses belong to the polyene and azole families. The polyenes form a large family of drugs derived from Streptomycete species but only three, amph’otericin B, nystatin and natamycin, are used against human infections.4 The former two have a broad range of antifungal activity which includes the major pathogens involved in systemic mycoses, apart from the zygomycete fungi. Natamycin is less frequently used but is active against dermatophytes as well as other pathogens, including aspergilli. It is available in topical form and in solution for nebulization. Only amphotericin B, of the whole series, can be given intravenously but it is potentially toxic.’ Reservations also exist because of reports of amphotericin B-resistance in some yeast pathogens in immunocompromised patients6 and poor bioavailability of the drug in infected tissue.7 The azoles are a rapidly expanding family of drugs.* The first group to be developed, the imidazoles, contains a large number of compounds primarily aimed at topical use. The imidazole antifungals show a broad spectrum of inhibitory activity. They affect most of the common superficial fungal pathogens as well as many systemic agents. Few are active, however, against aspergilli and zygomycetes. The only members available for parenteral or systemic usage are miconazole, which can be administered intravenously, or ketoconazole which can be given orally. Both are poorly active against aspergilli. Clotrimazole is well absorbed following oral administration but it is a potent enzyme inducer and serum levels are greatly reduced after two weeks of therapy. It is still used occasionally in the USA in the troche form for oropharyngeal candida infections. Interestingly, it is active against aspergilli in vitro, but has not been used specifically for prophylaxis against this infection.’ There are at present two systemically active triazole antifungals, itraconazole and fluconazole, available for clinical use. Itraconazole is active against a broad spectrum of fungi with the possible exception of the zygomycetes. Fluconazole is more difficult to assess; in-vitro tests are reported not to reflect activity in viva” and it seems to be less active against mould fungi such as Aspergilih spp. although in some animal models the drug appears to act against aspergilli at higher doses.” The two main allylamines, naftifine and terbinafine are recent introductions.‘* While naftifine has both antifungal and anti-inflammatory activity, terbinafine is also fungicidal in vitro. l3 Although this activity covers a very wide range of fungi ii~ vitro, including some systemic dimorphic pathogens and Aspergillus species, in vim it only appears to be effective
462
Ft. J. Hay
against dermatophytes when given orally. No studies of these drugs as prophylactic agents against systemic pathogens have been published. There is also a large and miscellaneous group of antifungal agents, many of which are only available for topical use. Amongst the drugs used for systemic antifungal chemotherapy flucytosine is the most widely used. However, the frequency of resistance and other side effects such as bone marrow depression at high serum levels has made this a less desirable choice for treatment. The combination of flucytosine with amphotericin B is also a popular combination even though the evidence for its superior efficacy over amphotericin B on its own is really only established in the case of it has been used for both candida cryptococcal meningitis. l4 Nonetheless and aspergillus infections. At present little has been established about the efficacy of cilofungin. It appears to inhibit the incorporation of N-acetylglucosamine into the fungal cell wall. Its spectrum of activity is mainly directed against C. albicans and C. tropicalis. It is less active against related species of the same genus in vitro and unrelated fungi including aspergilli.” It also has to be given by the intravenous route. Few of this wide range of antifungals have been used for prophylaxis against fungi whose spores can be spread by the airborne route. For instance there is no data on oral non-absorbed amphotericin B, nystatin or ketoconazole in this context. Fluconazole does not appear to be a promising candidate either. By contrast there is is one study of the triazole, itraconazole, which suggests that it may have value as a prophylactic drug against Aspergillus, though the study is based on a recent but nonetheless historical comparison with ketoconazole. Here five patients receiving itraconazole during a period of neutropenia developed aspergillosis compared to 19 of those on ketoconazole. i6 The incidence of aspergillosis in this report is surprisingly high but nonetheless the striking difference between control and itraconazole-treated groups has to explained. Failure of prophylaxis in the itraconazole group was thought to be related to poor absorption producing serum drug levels of less than 0.25 mg 1-l. Further studies in this area have confirmed that absorption of itraconazole is impaired in the neutropenic patient receiving intensive cytostatic therapy.” This is also known to affect the absorption of ketoconazole. One further approach which can be used to prevent serious morbidity due to aspergillus infections is the use of early empirical therapy when there is antibiotic resistant fever. There have been a number of randomized studies using this approach. The first showed fewer invasive fungal infections in those receiving amphotericin B although these were mainly due to Candida.‘8 The second also showed differences in the frequency of invasive mycoses although not in resolution of fever, particularly in patients who had not received oral prophylaxis with polyene antifungals and in patients over of aspergillus infections, the age of 1.5 years. l9 Given the high mortality particularly where treatment is delayed,*’ other methods of drug delivery of
Chemoprophylaxis
higher concentrations may further improve
of amphotericin empirical therapy Alternative
of fungal
infection
B such as liposome for aspergillosis.21,22
approaches
463
encapsulation
to therapy
Enilconazole Enilconazole is a new broad spectrum antifungal imidazole which is reported to be fungicidal in vitro. It is active topically against dermatophyte infections in experimentally infected animals. However, it is also effective in vitro against Aspergillus species. It can be used in vapour phase and has been employed to treat chickens with air sac aspergillosis. If Aspergillus fumigatus conidia were placed in petri dlishes in a room fumigated with enilconazole, whose vapour phase was generated in a smoke generator, complete inhibition of fungi was seen in 6/8 hanging drop suspensions at a drug concentration of 0.254 g m-“. The room in which the experiment was carried out was 59 m3 in volume and this was adequately covered by three of generators. 23 In human contacts it has been employed in the fumigation swimming pools to control transmission of athlete’s foot.24 In chicken houses enilconazole has been employed in the presence of the birds as treatment and no toxicity has been observed.25 The recommended ratio of generator to volume is one generator to 50m3. No reports of the use of enilconazole in human prophylaxis or even the treatment of ward areas contaminated with aspergilli are available, but this may be a potentially useful approach. Amphotericin B by inhalation or nasal insuflation Amphotericin B has long been used for the primary treatment of systemic fungal infections by the intravenous route. In some countries, including the UK, it is also available and used as an oral non-absorbed prophylactic drug in neutropenic patients. The polyenes, amphotericin B,26 nystatin27 and natamycin, 28 have all been used as therapy for pulmonary mycoses by nebulization with varying results. Best responses have been seen in patients heavily colonized with aspergilli where the clinical value of such an approach may be questionable. In another study it was used as an intranasal prophylactic treatment in patients with neutropenia and fever. Of 28 patients receiving the drug only one developed invasive pulmonary aspergillosis compared to S/30 of those on placebo.29,30 The amphotericin B was administered via a nasal spray. This approach depends critically on the tolerability of the preparation (usually good) and the size of particle generated. Droplets less than 4 pm are needed in order to penetrate to the terminal airways. In addition it is necessary to confirm that application of a spray to the nasal mucosa is an appropriate site as a significant number of patients with invasive pulmonary aspergillosis do not have positive nasal cultures.31 There is also evidence that in an experimental infection in rats due to Aspergillus treatment with aerosolized amphotericin B caused early
464
R. J. Hay
and rapid recovery although the responses were not as high as those seen with amphotericin B given by the parenteral route. Conclusion
Some of the methods described above offer potential ways of prevention of systemic infections due to fungi which are disseminated by the airborne route, for instance during building work associated with hospitals. However, few of those discussed have undergone clinical trials with this specific indication in mind and their role in infections other than those due to Aspergillus spp. is unexplored. Although infections due to Candida spp. are generally the most systemic mycoses seen in common immunocompromised patients, in some units invasive aspergillosis is seen more frequently and in episodes of hospital infection associated with building work A. fumigatus may dominate the scene. Further work in this field is clearly needed. References I. Meunier F. Prevention of mycoses in immunocompromised patients. Rev Infect Dis 1987; 9: 4088415. 2. Polak A. Mode of action of morpholine derivatives. Ann NY Acad Sci 1988; 544: 221-228. 3. Debono M, Abbott BJ, Turner JR et al. Synthesis and evaluation of LY 121019, a member of a series of semisynthetic analogues of the antifungal lipopeptide, echinocandin B. Ann NY Acad Sci 1988; 544: 141-151. In Speller DCE, Ed. Antifungal 4. Medoff G, Kobayashi GA. The polyenes. Chemotherapy. John Wiley and Sons: Chichester 1980; 3-34. 5. Miller R, Bates JH. Amphotericin B toxicity. A follow-up report of 53 patients. Ann Intern Med 1969; 71: 1090-1095. 6. Powderly WG, Kobayashi GS, Herzig GP, Medoff G. Amphotericin B-resistant yeast infection in severely immunocompromised patients. AmJ Med 1988; 84: 826-832. 7. Christiansen KJ, Bernard EM, Gold JWM, Armstrong D. Distribution and activity of amphotericin B m humans. J Inject Dis 1985; 152: 1037-1043. 8. Fromtling RA. Overview of medically important antifungal azole derivatives. CZin Microbial Rev 1988; 1: 187-217. C, Schweitzer R et al. Prophylaxis of oral candidiasis with oral 9. Owens M, Nightingale clotrimazole. Arch Intern Med 1984; 144: 290-293. MS, Richardson K. The discovery and mode of action of fluconazole. In: IO. Marriott Fromtling RA, Ed. Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: JR Prous Publishers 1987; 81-92. TF, Miniter P, Andriole VT. Efficacy of fluconazole in experimental II. Patterson aspergillosis. Rev Infect Dis 1990; 12 (Suppl. 3): S281-S285. 12. Petranyi G, Meingassner JG, Mieth H. Antifungal activity of the allylamine derivative, terbinafine, in vitro. Antimicrob Agents Chemother 1987; 31: 1365-1368. 13. Shadomy S, Espinel Ingroff A, Gebhart RJ. In vitro studies with SF 86-327, a new orallv active allvlamine derivative. Sabouraudiu 1985: 23: 125-132. WE,, Duma RJ et al. A comparison of amphotericin B alone and 14. Bennett JE, Dismukes combined with flucytosine m the treatment of cryptococcal meningitis. N Engl J Med 1979: 301: 126-131. LC, Alborn WE, Debono M. Anti-Candida activity 15. Gordee RS, Zeckner DJ, Howard and toxicology of LYI21019, a novel semisynthetic polypeptide antifungal antibiotic. Ann NY Acad Sci 1988; 544: 294-310. 16. Tricot G. Joosten E, Boogaerts MA, Van de Pitte J, Cauwenbergh G. Ketoconazole vs
Chemoprophylaxis
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
of fungal
infection
465
itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of two nonrandomized studies. Rev Infect Dis 1987; 7 (Suppl. 1): 94-99. Boogaerts MA, Van de Pitte K, Verheof G, Zachee P, de Beule K. Itraconazole prophylaxis of invasive fungal infections in prolonged neutropenia. Abstract No 576. 28th Interscience Conference on Antimicrobial Agents and Chemotherapy 1988. Pizzo PA, Robichaud KJ, Gill FA, Witebsky F. Empiric antibiotic and antifungal therapy for cancer patients with Iprolonged fever and granulocytopenia. AmJ Med 1982; 72: 101-l 10. EORTC. Empirical antifungal therapy in febrile granulocytopenic patients. Am J Med 1989; 86: 668-672. Aisner J, Murillo J, Schimpff SC, Steere AC. Invasive aspergillosis in acute leukemia: correlation with nose cultures and antibiotic use. Ann Intern Med 1979; 90: 4-9. Lopez-Berestein G, Fainstein V, Hopfer R et al. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study. J Infect Dis 1985; 151: 704-710. Sculier J-P, Coune A, Meunier F et aE. Pilot study of amphotericin B entrapped in sonicated liposomes in cancer patients with fungal infections. Eur J Cancer CZin Oncol 1988; 24: 527-538. van Cutsem, Van Gerven F, Janssen PAJ. In vitro activity of enilconazole against Aspergillus spp. and its fungicidal efficacy in a smoke generator against Aspergillus fumigatus. Mycoses 1989; 31: 143-147. van Cutsem JV, DE Vriendt H, Van Hoorebeke C, Rochette F. Pilzflora in offentlichen Hallenbadern. Empfindlichkeit fur Enilconazol. Archiv des Badewesens. Heft 1988; 9/10. Desplenter L. Aspergillosis in animal health: environmental control. In: Vanden Bossche H, MacKenzie DWR, Cauwenbergh G, Eds. AspergiZlus and Aspergillosis. New York: Plenum Press 1988; 289-2:97. Slavin RG, Laird TS, Cherry JD. Allergic bronchopulmonary aspergillosis in a child. J Pediatr 1970; 76: 416421. Black JM. Pulmonary aspergillosis. PYOC Roy Sot Med 1960; 53: 974975. Edwards G, La Touche CJP. The treatment of bronchopulmonary mycoses with a new antibiotic-pimaricin. Lancet 1964; 1: 1349-1353. Meunier F, Leleux A, Gerain J et al. Prophylaxis of aspergillosis in neutropenic cancer patients with nasal spray of amphotericin B: a prospective randomised clinical study. Abstract 1346. Proceedings of thle 27th ICAAC Meeting 1987. Meunier F. New methods for delivery of antifungal agents. Rev Infect Dis 1989; 11 (Suppl. 7): S1605-S1612. Aisner J, Schimpff SC, Wiernik PH. Treatment of invasive aspergillosis. Relationship of early diagnosis and treatment to response. Ann Intern Med 1977; 90: 539-543. Schmitt HJ, Bernard EH, Hauser M, Armstrong D. Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis. Antimicrob Agents Chemother 1988; 32: 1676-l 679.
A), 460-465
The role of chemoprophylaxis in the prevention airborne infection by fungal pathogens
of
R. J. Hay Department
of Dermatology,
Guys
Hospital,
London
SE1
9RT,
UK
Summary: The main approach to prevention of infection following airborne transmission of pathogenic fungi such as Aspergillus species has been environmental. However, there are a number of potentially effective methods of prophylaxis using antifungal drugs. Those described previously include itraconazole or amphotericin B given by the intranasal or intrapulmonary route after nebulization. Another possibility for investigation in the future is enilconazole which is highly active against aspergilli after inhalation in animals and which has been used in the treatment of aspergillosis in poultry. Keywords: Aspergillus;
Candida; antifungal
drugs;
chemoprophylaxis.
Introduction
The use of drugs to anticipate and thereby prevent the invasion of fungi in immunocompromised patients has long formed part of the strategy of the management of this group, but has also been the subject of scepticism and controversy. While generally the target organism is Candidu al&cans, whose presumed principal site of entry is the gastrointestinal tract, the evaluation of the use of regimens aimed at reducing the risk of invasion is difficult to Many studies have contained too few patients to perform and interpret.’ form a valid view of the success of the approach and the diagnosis of invasive candidosis in the group at most risk, the neutropenic patient, is itself difficult because of the lack of clinical signs and symptoms and the inaccuracy of present methods of laboratory diagnosis. Where, in such studies, proven invasive fungal infections have occurred the numbers have usually been too small to compare with any degree of statistical accuracy. Chemoprophylaxis aimed at other fungi has not generally been the subject of much research even though there are many reasons why this should be a valid approach. The purpose of this paper is to explore the potential role of protection of patients at risk from airborne infection due to other fungi, particularly Aspergillus spp., using drugs. The
antifungal
agents
The selection of drugs for chemoprophylaxis that are effective in a wider range of fungal infections is clearly important. There are three major 0195S6701/91/06A460+06
$03.00/O
0 1991 The Hospital
460
Infection
Society
Chemoprophylaxis
of fungal
infection
461
families of antifungal drugs: the polyenes, the azoles and the allylamines. In addition there is a miscellaneous group of compounds such as flucytosine and griseofulvin which do not belong to a single family of drugs. There are also new groups of antifungals, under development such as the morpholines* (amorolfine) and the echinocandins such as cilofungin.3 However, the principal antifungals used against the systemic mycoses belong to the polyene and azole families. The polyenes form a large family of drugs derived from Streptomycete species but only three, amph’otericin B, nystatin and natamycin, are used against human infections.4 The former two have a broad range of antifungal activity which includes the major pathogens involved in systemic mycoses, apart from the zygomycete fungi. Natamycin is less frequently used but is active against dermatophytes as well as other pathogens, including aspergilli. It is available in topical form and in solution for nebulization. Only amphotericin B, of the whole series, can be given intravenously but it is potentially toxic.’ Reservations also exist because of reports of amphotericin B-resistance in some yeast pathogens in immunocompromised patients6 and poor bioavailability of the drug in infected tissue.7 The azoles are a rapidly expanding family of drugs.* The first group to be developed, the imidazoles, contains a large number of compounds primarily aimed at topical use. The imidazole antifungals show a broad spectrum of inhibitory activity. They affect most of the common superficial fungal pathogens as well as many systemic agents. Few are active, however, against aspergilli and zygomycetes. The only members available for parenteral or systemic usage are miconazole, which can be administered intravenously, or ketoconazole which can be given orally. Both are poorly active against aspergilli. Clotrimazole is well absorbed following oral administration but it is a potent enzyme inducer and serum levels are greatly reduced after two weeks of therapy. It is still used occasionally in the USA in the troche form for oropharyngeal candida infections. Interestingly, it is active against aspergilli in vitro, but has not been used specifically for prophylaxis against this infection.’ There are at present two systemically active triazole antifungals, itraconazole and fluconazole, available for clinical use. Itraconazole is active against a broad spectrum of fungi with the possible exception of the zygomycetes. Fluconazole is more difficult to assess; in-vitro tests are reported not to reflect activity in viva” and it seems to be less active against mould fungi such as Aspergilih spp. although in some animal models the drug appears to act against aspergilli at higher doses.” The two main allylamines, naftifine and terbinafine are recent introductions.‘* While naftifine has both antifungal and anti-inflammatory activity, terbinafine is also fungicidal in vitro. l3 Although this activity covers a very wide range of fungi ii~ vitro, including some systemic dimorphic pathogens and Aspergillus species, in vim it only appears to be effective
462
Ft. J. Hay
against dermatophytes when given orally. No studies of these drugs as prophylactic agents against systemic pathogens have been published. There is also a large and miscellaneous group of antifungal agents, many of which are only available for topical use. Amongst the drugs used for systemic antifungal chemotherapy flucytosine is the most widely used. However, the frequency of resistance and other side effects such as bone marrow depression at high serum levels has made this a less desirable choice for treatment. The combination of flucytosine with amphotericin B is also a popular combination even though the evidence for its superior efficacy over amphotericin B on its own is really only established in the case of it has been used for both candida cryptococcal meningitis. l4 Nonetheless and aspergillus infections. At present little has been established about the efficacy of cilofungin. It appears to inhibit the incorporation of N-acetylglucosamine into the fungal cell wall. Its spectrum of activity is mainly directed against C. albicans and C. tropicalis. It is less active against related species of the same genus in vitro and unrelated fungi including aspergilli.” It also has to be given by the intravenous route. Few of this wide range of antifungals have been used for prophylaxis against fungi whose spores can be spread by the airborne route. For instance there is no data on oral non-absorbed amphotericin B, nystatin or ketoconazole in this context. Fluconazole does not appear to be a promising candidate either. By contrast there is is one study of the triazole, itraconazole, which suggests that it may have value as a prophylactic drug against Aspergillus, though the study is based on a recent but nonetheless historical comparison with ketoconazole. Here five patients receiving itraconazole during a period of neutropenia developed aspergillosis compared to 19 of those on ketoconazole. i6 The incidence of aspergillosis in this report is surprisingly high but nonetheless the striking difference between control and itraconazole-treated groups has to explained. Failure of prophylaxis in the itraconazole group was thought to be related to poor absorption producing serum drug levels of less than 0.25 mg 1-l. Further studies in this area have confirmed that absorption of itraconazole is impaired in the neutropenic patient receiving intensive cytostatic therapy.” This is also known to affect the absorption of ketoconazole. One further approach which can be used to prevent serious morbidity due to aspergillus infections is the use of early empirical therapy when there is antibiotic resistant fever. There have been a number of randomized studies using this approach. The first showed fewer invasive fungal infections in those receiving amphotericin B although these were mainly due to Candida.‘8 The second also showed differences in the frequency of invasive mycoses although not in resolution of fever, particularly in patients who had not received oral prophylaxis with polyene antifungals and in patients over of aspergillus infections, the age of 1.5 years. l9 Given the high mortality particularly where treatment is delayed,*’ other methods of drug delivery of
Chemoprophylaxis
higher concentrations may further improve
of amphotericin empirical therapy Alternative
of fungal
infection
B such as liposome for aspergillosis.21,22
approaches
463
encapsulation
to therapy
Enilconazole Enilconazole is a new broad spectrum antifungal imidazole which is reported to be fungicidal in vitro. It is active topically against dermatophyte infections in experimentally infected animals. However, it is also effective in vitro against Aspergillus species. It can be used in vapour phase and has been employed to treat chickens with air sac aspergillosis. If Aspergillus fumigatus conidia were placed in petri dlishes in a room fumigated with enilconazole, whose vapour phase was generated in a smoke generator, complete inhibition of fungi was seen in 6/8 hanging drop suspensions at a drug concentration of 0.254 g m-“. The room in which the experiment was carried out was 59 m3 in volume and this was adequately covered by three of generators. 23 In human contacts it has been employed in the fumigation swimming pools to control transmission of athlete’s foot.24 In chicken houses enilconazole has been employed in the presence of the birds as treatment and no toxicity has been observed.25 The recommended ratio of generator to volume is one generator to 50m3. No reports of the use of enilconazole in human prophylaxis or even the treatment of ward areas contaminated with aspergilli are available, but this may be a potentially useful approach. Amphotericin B by inhalation or nasal insuflation Amphotericin B has long been used for the primary treatment of systemic fungal infections by the intravenous route. In some countries, including the UK, it is also available and used as an oral non-absorbed prophylactic drug in neutropenic patients. The polyenes, amphotericin B,26 nystatin27 and natamycin, 28 have all been used as therapy for pulmonary mycoses by nebulization with varying results. Best responses have been seen in patients heavily colonized with aspergilli where the clinical value of such an approach may be questionable. In another study it was used as an intranasal prophylactic treatment in patients with neutropenia and fever. Of 28 patients receiving the drug only one developed invasive pulmonary aspergillosis compared to S/30 of those on placebo.29,30 The amphotericin B was administered via a nasal spray. This approach depends critically on the tolerability of the preparation (usually good) and the size of particle generated. Droplets less than 4 pm are needed in order to penetrate to the terminal airways. In addition it is necessary to confirm that application of a spray to the nasal mucosa is an appropriate site as a significant number of patients with invasive pulmonary aspergillosis do not have positive nasal cultures.31 There is also evidence that in an experimental infection in rats due to Aspergillus treatment with aerosolized amphotericin B caused early
464
R. J. Hay
and rapid recovery although the responses were not as high as those seen with amphotericin B given by the parenteral route. Conclusion
Some of the methods described above offer potential ways of prevention of systemic infections due to fungi which are disseminated by the airborne route, for instance during building work associated with hospitals. However, few of those discussed have undergone clinical trials with this specific indication in mind and their role in infections other than those due to Aspergillus spp. is unexplored. Although infections due to Candida spp. are generally the most systemic mycoses seen in common immunocompromised patients, in some units invasive aspergillosis is seen more frequently and in episodes of hospital infection associated with building work A. fumigatus may dominate the scene. Further work in this field is clearly needed. References I. Meunier F. Prevention of mycoses in immunocompromised patients. Rev Infect Dis 1987; 9: 4088415. 2. Polak A. Mode of action of morpholine derivatives. Ann NY Acad Sci 1988; 544: 221-228. 3. Debono M, Abbott BJ, Turner JR et al. Synthesis and evaluation of LY 121019, a member of a series of semisynthetic analogues of the antifungal lipopeptide, echinocandin B. Ann NY Acad Sci 1988; 544: 141-151. In Speller DCE, Ed. Antifungal 4. Medoff G, Kobayashi GA. The polyenes. Chemotherapy. John Wiley and Sons: Chichester 1980; 3-34. 5. Miller R, Bates JH. Amphotericin B toxicity. A follow-up report of 53 patients. Ann Intern Med 1969; 71: 1090-1095. 6. Powderly WG, Kobayashi GS, Herzig GP, Medoff G. Amphotericin B-resistant yeast infection in severely immunocompromised patients. AmJ Med 1988; 84: 826-832. 7. Christiansen KJ, Bernard EM, Gold JWM, Armstrong D. Distribution and activity of amphotericin B m humans. J Inject Dis 1985; 152: 1037-1043. 8. Fromtling RA. Overview of medically important antifungal azole derivatives. CZin Microbial Rev 1988; 1: 187-217. C, Schweitzer R et al. Prophylaxis of oral candidiasis with oral 9. Owens M, Nightingale clotrimazole. Arch Intern Med 1984; 144: 290-293. MS, Richardson K. The discovery and mode of action of fluconazole. In: IO. Marriott Fromtling RA, Ed. Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: JR Prous Publishers 1987; 81-92. TF, Miniter P, Andriole VT. Efficacy of fluconazole in experimental II. Patterson aspergillosis. Rev Infect Dis 1990; 12 (Suppl. 3): S281-S285. 12. Petranyi G, Meingassner JG, Mieth H. Antifungal activity of the allylamine derivative, terbinafine, in vitro. Antimicrob Agents Chemother 1987; 31: 1365-1368. 13. Shadomy S, Espinel Ingroff A, Gebhart RJ. In vitro studies with SF 86-327, a new orallv active allvlamine derivative. Sabouraudiu 1985: 23: 125-132. WE,, Duma RJ et al. A comparison of amphotericin B alone and 14. Bennett JE, Dismukes combined with flucytosine m the treatment of cryptococcal meningitis. N Engl J Med 1979: 301: 126-131. LC, Alborn WE, Debono M. Anti-Candida activity 15. Gordee RS, Zeckner DJ, Howard and toxicology of LYI21019, a novel semisynthetic polypeptide antifungal antibiotic. Ann NY Acad Sci 1988; 544: 294-310. 16. Tricot G. Joosten E, Boogaerts MA, Van de Pitte J, Cauwenbergh G. Ketoconazole vs
Chemoprophylaxis
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
of fungal
infection
465
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