I
MYCOSES
35, 225-228 (1992)
ACCEPTED: NOVEMBER 13, 1991
Fungal infections in surgical patients Pilzinfektionen bei chirurgischen Patienten P. Kujath Key words. Deep mycosis, invasive candidosis, abdominal surgery, peritoneal lavage, antimycotic chemotherapy, fluconazole, amphotericin B, 5-fluorocytosine. Schliisselworter. Endomykose, invasive Candidose, Abdominalchirurgie, Peritoneallavage, antimykotische Chemotherapie, Fluconazol, Amphotericin B, 5-Fluorcytosin.
Summary. Deep fungal infection was diagnosed in 42 patients (a rate of four per 1000) treated during a one-year period between 1988 and 1989 at the Surgical Clinic in Wurzburg. Most occurred in association with damage to intraabdominal hollow organs. Diagnosis of deep fungal infections is difficult and only histological identification provides definite proof. However, often the decision to treat has to be made on the basis of the clinical picture and the physician’s subjective assessment. Combination treatment with amphotericin B and 5-fluorocytosine is still the current recommendation but the introduction of the azole antifungal agents appears likely to bring about a change. A trial of fluconazole showed it to have clear advantages over combination treatment, being effective, well tolerated and easily administered. Zusammenfassung. Tiefe Pilzinfektionen wurden bei 42 Patienten diagnostiziert (eine Rate von vier pro 1000), die wahrend einer einjahrigen Periode, zwischen 1988 und 1989, in der Chirurgischen Klinik in Wiirzburg behandelt wurden. Die meisten tiefen Pilzinfektionen traten in Verbindung mit einer Schadigung der intraabdominalen Hohlorgane auf. Ihre Diagnose ist jedoch sehr schwierig. Ein eindeutiger Nachweis 1aRt sich nur durch die histologische Untersuchung erbringen. Oft muR jedoch der EntschiuR zu behandeln, auf der Basis des klinischen Biides und der subjektiven Beurteilung des Arztes Klinik fur Chirurgie, Universitat Liibeck, Germany. Correspondence: Prof. Dr P. Kujath, Chirurgische Universitatsklinik, Ratzeburger Allee 160, D-W-2400 Liibeck, Germany.
getroffen werden. Zur Zeit wird noch die Kombinationstherapie mit Amphotericin B und 5-Fluorcytosin empfohlen, obwohl sich durch die Einfuhrung der Azol-Antimykotika moglicherweise eine Xnderung abzuzeichnen beginnt. Anhand eines Versuches mit Fluconazol lien sich zeigen, daR es gegenuber der Kombinationstherapie eindeutige Vorteile besitzt, indem es wirksam, gut vertraglich und leicht zu verabreichen ist. Introduction
The dangers of secondary fungal infection and its complications are of increasing significance in surgery [ 1-41. Therefore, answers to the following four questions concerning this type of infection are of great importance to the clinician: (1) What is the epidemiology of the infection?; (2) Is the infection superficial and localized or deep and disseminated?; (3) When is treatment to be started?; and (4) What drug or combination of drugs is to be used in treatment?
Clinical monitoring and observations Epidemiology Fungi are involved in 5-10% of infections. Between 1980 and 1990, 344,610 pathogenic microorganisms were identified by the Nosocomial Infection Surveillance System; 7.9% were fungi, of which 79% were Candida spp. (Jarvis WR, paper presented at the 3rd Conference on Nosocomial Infections, Atlanta, 1990). Graybill reported that detected fungaemia increased more than ten-fold between 1977 and 1988 among
226
P. KUJATH
predominantly medical patients [5]. Just under 10,000 patients were treated at the University Surgical Clinic in Wiirzburg in the year between November 1, 1988 and October 31, 1989 (the study period), among whom a total of 3342 microbiological tests were performed. Additional mycological diagnosis was requested for 1447 patients (43.2%). A total of 429 positive results were obtained in 90 patients. Deep fungal infection was diagnosed in 42 (a rate of four per 1000 patients). Risk factors play a major role in the occurrence of fungal infection, but they differ between medical and surgical patients. All 42 patients with deep fungal infection diagnosed during the study period were operated on and an analysis based on pre-existing risk factors showed about 73% had had conditions affecting intra-abdominal organs (Table 1). I t was also found that 50% of the patients were over 60 years ofage, 12 (28.5%) were underweight or grossly overweight, 12 (28.5%) had malignant tumours and 9 (21.4%) had diabetes mellitus (Table 1). The fungal organisms isolated were Candida albicans (35 cases), C. tropicalis (6 cases), Torulopsis glabrata (4 cases), C. parapsilosis (3 cases), and Aspergillus fumigatus (2 cases). The apparent excess in the
Table 1. Risk factors among the patients with deep fungal infection studied at the University Surgical Clinic in Wiirzburg between November 1, 1988 and October 31, 1989
Risk factor
n
%
Operationlwound areas Antibiotic therapy Damage to intra-abdominal hollow organs Perforated/penetrating ulcer Tumour Perforation following trauma Suture insufficiency Necrosis (incarceration, rnesenteric infarction) Intensive care Central venous catheter Tracheostorny/long-term assisted respiration Parenteral feeding Bladder catheter Nasal tube Age ( > 60 years) Underweight or substantial increase in weight Malignant turnour Diabetes rnellitus Alcohol abuse Concomitant infectious disease Chemotherapy, immunosuppression, glucocorticoids, leukaernia, radiotherapy, leucopenia
42 38
100
5
90.4 73.8 21.4 16.6 14.2 11.9
4 28 28
9.5 66.6 66.6
25 25 25 7 21
59.5 59.5 59.5
12
28.5 28.5 21.4
31 9 7
6
12 9 3 3
0
16.6 50.0
7.1 7.1
0
number of organisms over the number of patients was accounted for by mixed infections. The conclusion from an analysis of the findings during the study period are that fungal infections in surgical patients are mainly found in association with damage to intra-abdominal hollow organs and that the organism are mostly present at the start of the surgical treatment. An essential question is the extent to which Candida infections occur in an intensive care ward. Twelve patients who were in our intensive care ward for more than 40 days were monitored serologically every five days. Although there were substantial fluctuations in antigen and antibody titres in all patients, none developed a clinical deep fungal infection.
Case histov
It was possible to identify the route of infection in individual patients. For example, a 56-yearold alcoholic with cirrhosis of the liver suffered a perforated gastric ulcer. H e underwent gastric resection (Billroth 11). Extensive fungal colonies were found in the necrotic tissue at the base of the ulcer in the surgical specimen. After transient insufficiency at the anastomosis, which was oversewn, small fungal granulomata were found on peritoneal biopsy. Much larger granulomata were discovered at a subsequent laparotomy. The patient developed pronounced generalized Candida peritonitis and died from Candida sepsis.
Diagnosis The diagnosis of a deep fungal infection poses a problem in that only the histological identification of an invasive growth provides the ultimate proof. Therefore, a specimen for histological examination should be taken whenever possible where a positive microbiological diagnosis has been made. For example, the histological examination of a small piece of tracheal biopsy material allows a deep fungal infection to be differentiated from the superficial fungal infection that commonly occurs in ventilated patients. Opinions on the significance of serological tests vary. Antibody tests such as the complement fixing reaction and the haemagglutination test are difficult to evaluate. Several antigen tests are currently available. Phillips and co-workers have expressed specificity of 43% [6]. I n contrast, Walsh and co-workers found the detection of circulating Candida enolase to have a sensitivity of 54% which rose to 85% after several repetitions [7]. mycoses 35, 225-228 (1992)
FUNGAL INFECTIONS IN SURGICAL PATIENTS
Treatment
Table 3. Eradication of fungus from specimen material
Since the detection of a deep fungal infection is not always possible, clinical and the subjective assessment of the treating physician play a part in making the decision to treat. However, the following are definite indications for starting antifungal treatment: ( 1) The histological detection of a deep fungal infection, (2) a positive blood culture, (3) a rising serological antibody titre and the detection of antigen, and (4)a life-threatening clinical picture. I t should also be borne in mind that all critically ill patients are prone to fungal infection and that infection can be of particular danger in these cases. The standard treatment for life-threatening fungal infection is still considered to be a combination of amphotericin B with 5-fluorocytosine [8]. However, the development of the azole antifungal agents has created new possibilities. Since fluconazole, a bis-triazole antifungal drug, is able to penetrate into all tissues and is effective against C. albicans we decided to use this agent in the treatment of our surgical patients. Between March 1 and October 31, 1988, 26 patients with deep secondary fungal infection, including 15 with peritoneal invasion, were treated with fluconazole; 22 were cured (Table 2). Colonization by Candida was totally eradicated within 12 days in more than half the patients (Table 3) [9]. Since fluconazole has only moderate activity against Candida yeasts in vitro, the monitoring of fluconazole therapy by histological examination has been studied by means of programmed peritoneal lavage [lo]. Within this study 10 patients with Candida peritonitis were treated during the period beginTable2. Mycological response to therapy at the end of treatment Principal infective focus
Patients (n)
Cured*
Peritoneum (1ocalized)t Peritoneum (generalized)$ Trachea Wound area Lungs Oesophagus Skin Necrotic retroperitoneal cavity
12
11 1 3
Total
26
3 3 3 2 1 1 1
over time Day of treatment
Cumulative percentage of microscopically and culturally negative specimens
6
27
9 12
46
15
69
18 21
81 85
54
ning May 1, 1988, to January 1, 1990. Origins of the infection were lesions and perforations of the gastrointestinal tract. The diseases were favoured by the risk factors malignancy, diabetes mellitus and extensive antibacterial chemotherapy. The mean Apache score [ 111 was 19.0. All the patients were operated on again on the grounds of a diagnosis of diffuse peritonitis and programmed peritoneal lavage was instituted. The diagnosis of Candida peritonitis was made from the microbiological findings, serological results, tissue histology (Fig. 1 ) and the clinical picture. Five of the 10 patients died from their underlying disease, even though the fungal peritonitis had been controlled. Daily laparotomy enabled histological checks to be made on the progress of the Candida peritonitis [12]. After fluconazole had been administered, the fungal elements became swollen and reduced in number within two to four days (Fig. 2).
A comparative study Since it appeared that fluconazole was able to destroy most of the invading Candida cells within 4 days (Fig. 2) a therapeutic study was undertaken in which fluconazole in a dose of 300 mg
(n)
2 2 1 1 1 22
*Cured=Five specimens taken up to four weeks after the end of treatment, negative on microscopy and culture. t Intestinal anastomosis 7; peritoneal abscess 3; drainage tube 2. $Fungal peritonitis 3.
mycoses 35, 225-228 (1992)
227
Figure 1. Viable blastospores and mycelia prior to onset of therapy with fluconazole. The peritoneum is invaded by fungi.
228
P.KUJATH
infection in surgical patients. The drug is highly effective against C. albicans, the most important fungal species pathogenic to man. Fluconazole has clear advantages over combination treatment with amphotericin B and 5-fluorocytosine on account of its good tolerability and ease of administration. Thus, the indications for prescribing an antifungal agent can be widened. Consideration must also be given to whether an antifungal agent may be given prophylactically to critically ill patients with underlying diseases such as tumours, diabetes mellitus or alcohol abuse, and particularly to patients with duodenal perforations. Four days post onset of therapy. Only foci of Cundidu blastospores markedly reduced in number with minimal mycelia can be detected; the oval blastospores exhibit hydropic changes and bullous distention. Pseudomycelia are fragmented.
Figure 2.
’
intravenously daywas compared against amphotericin B in a dose of up to 0.6 mg kg-’ body weight day- combined with 5-fluorocytosine in a dose of 2.5 g, three times a day. Patients who suffered from a deep fungal infection (as described above) were admitted to the study and randomized to treatment. Patients who did not give their consent, who were pregnant or who had previously received antifungal therapy were excluded, as were those in the terminal stages of disease. Of the 73 patients evaluated to date, 12 have been treated with the combination of amphotericin B and 5-fluorocytosine and 11 with fluconazole; all had undergone surgery and 18 had had leakage from the gastrointestinal tract. The two groups were comparable in age, height and weight. No fungi were detectable in the patients treated with amphotericin B/5-fluorocytosine after 8.3 days, and none were detectable in those treated with fluconazole after 12.2 days. Treatment had to be discontinued in one patient in the amphotericin B/5-fluorocytosine group on account of renal failure. Among the patients treated with fluconazole, the infection persisted in one case of Candidu peritonitis until the sixth day when the patient died. A clear improvement in mycological findings was otherwise evident in all patients. Six patients died, three in each group.
’
References Fegeler, W. (1983) Epidemiologie und Pathogenese generalisierender einheimischer Mykosen. Hrsg. Meinhof W., Schonfeld, H., Seeliger, H., Wegmann, T. Hahnenklee-Symposium 1982 “Systemische Mykosen”, Grenzach-Wyhlen, Roche, 19. Newman, F. & Rakower, S. (1978) The risk of positive cultures for Cundidu in the critically ill patient. Crif. Cure Med. 6 , 73-76. Solomkin, J., Flohr, A. & Simmons, R. (1982) Cundida infections in surgical patients. Ann. Surg. 195, 172-185. Young, R., Bennet, J., Geelhoed, G. cf ul. (1974) Fungemia with compromised host resistance. A study of 70 cases. Ann. Intern. Med. 80, 605-612. Graybill, J. R. & Sharkey, P. K. (1990) Fungal infections and their management. Br. J . Clin. Prucf. 44 (suppl 71), 23-3 1. Phillips, P., Dowd, A., Jewesson, P. el ul. (1990) Nonvalue of antigen detection immunoassays for diagnosis of candidemia. J. Clin. Microbiol. 28, 2320-2326. Walsh, T. J., Hathorn, J., Sobel, J. D. ef ul. (1991) Detection of circulating Cundidu enolase by immunoassay in patients with cancer and invasive candidiasis. N. Engl. J. Med. 324, 1026-1031. Perfect, J. R. (1991) Antifungal therapy and its use in surgical treatment. Surg. Cynec. Obsfef.171, 41-48. Kujath, P. & Lerch, K. (1989) New antimicrobial agents under clinical investigation: secondary mycosis in surgerv: treatment with fluconazole. Infecfion17. 56-63. 10 k e i n , E., Klaue, P. & Arbogast, R. (1983) Programmierte Peritoneallavage bei diffuser Peritonitis. Chirurg 54: 306-310. 1 1 Knaus, W. A., Zimmermann, J. E., Wagner, D. P., Draper, E. & Lawrence, D. Apache-acute physiology and chronic health evaluation: a physiologically based classification system. Crif. Care Med. 9, 591-597. 12 Kujath, P., Lerch, K. & Dammrich, J. (1990) Fluconazole monitoring in Cundidu peritonitis based in histological control. Mycoses 33, 441-448.
Conclusion The introduction of fluconazole has opened up new possibilities in the treatment of deep fungal
mycoses 35, 225-228 (1992)
MYCOSES
35, 225-228 (1992)
ACCEPTED: NOVEMBER 13, 1991
Fungal infections in surgical patients Pilzinfektionen bei chirurgischen Patienten P. Kujath Key words. Deep mycosis, invasive candidosis, abdominal surgery, peritoneal lavage, antimycotic chemotherapy, fluconazole, amphotericin B, 5-fluorocytosine. Schliisselworter. Endomykose, invasive Candidose, Abdominalchirurgie, Peritoneallavage, antimykotische Chemotherapie, Fluconazol, Amphotericin B, 5-Fluorcytosin.
Summary. Deep fungal infection was diagnosed in 42 patients (a rate of four per 1000) treated during a one-year period between 1988 and 1989 at the Surgical Clinic in Wurzburg. Most occurred in association with damage to intraabdominal hollow organs. Diagnosis of deep fungal infections is difficult and only histological identification provides definite proof. However, often the decision to treat has to be made on the basis of the clinical picture and the physician’s subjective assessment. Combination treatment with amphotericin B and 5-fluorocytosine is still the current recommendation but the introduction of the azole antifungal agents appears likely to bring about a change. A trial of fluconazole showed it to have clear advantages over combination treatment, being effective, well tolerated and easily administered. Zusammenfassung. Tiefe Pilzinfektionen wurden bei 42 Patienten diagnostiziert (eine Rate von vier pro 1000), die wahrend einer einjahrigen Periode, zwischen 1988 und 1989, in der Chirurgischen Klinik in Wiirzburg behandelt wurden. Die meisten tiefen Pilzinfektionen traten in Verbindung mit einer Schadigung der intraabdominalen Hohlorgane auf. Ihre Diagnose ist jedoch sehr schwierig. Ein eindeutiger Nachweis 1aRt sich nur durch die histologische Untersuchung erbringen. Oft muR jedoch der EntschiuR zu behandeln, auf der Basis des klinischen Biides und der subjektiven Beurteilung des Arztes Klinik fur Chirurgie, Universitat Liibeck, Germany. Correspondence: Prof. Dr P. Kujath, Chirurgische Universitatsklinik, Ratzeburger Allee 160, D-W-2400 Liibeck, Germany.
getroffen werden. Zur Zeit wird noch die Kombinationstherapie mit Amphotericin B und 5-Fluorcytosin empfohlen, obwohl sich durch die Einfuhrung der Azol-Antimykotika moglicherweise eine Xnderung abzuzeichnen beginnt. Anhand eines Versuches mit Fluconazol lien sich zeigen, daR es gegenuber der Kombinationstherapie eindeutige Vorteile besitzt, indem es wirksam, gut vertraglich und leicht zu verabreichen ist. Introduction
The dangers of secondary fungal infection and its complications are of increasing significance in surgery [ 1-41. Therefore, answers to the following four questions concerning this type of infection are of great importance to the clinician: (1) What is the epidemiology of the infection?; (2) Is the infection superficial and localized or deep and disseminated?; (3) When is treatment to be started?; and (4) What drug or combination of drugs is to be used in treatment?
Clinical monitoring and observations Epidemiology Fungi are involved in 5-10% of infections. Between 1980 and 1990, 344,610 pathogenic microorganisms were identified by the Nosocomial Infection Surveillance System; 7.9% were fungi, of which 79% were Candida spp. (Jarvis WR, paper presented at the 3rd Conference on Nosocomial Infections, Atlanta, 1990). Graybill reported that detected fungaemia increased more than ten-fold between 1977 and 1988 among
226
P. KUJATH
predominantly medical patients [5]. Just under 10,000 patients were treated at the University Surgical Clinic in Wiirzburg in the year between November 1, 1988 and October 31, 1989 (the study period), among whom a total of 3342 microbiological tests were performed. Additional mycological diagnosis was requested for 1447 patients (43.2%). A total of 429 positive results were obtained in 90 patients. Deep fungal infection was diagnosed in 42 (a rate of four per 1000 patients). Risk factors play a major role in the occurrence of fungal infection, but they differ between medical and surgical patients. All 42 patients with deep fungal infection diagnosed during the study period were operated on and an analysis based on pre-existing risk factors showed about 73% had had conditions affecting intra-abdominal organs (Table 1). I t was also found that 50% of the patients were over 60 years ofage, 12 (28.5%) were underweight or grossly overweight, 12 (28.5%) had malignant tumours and 9 (21.4%) had diabetes mellitus (Table 1). The fungal organisms isolated were Candida albicans (35 cases), C. tropicalis (6 cases), Torulopsis glabrata (4 cases), C. parapsilosis (3 cases), and Aspergillus fumigatus (2 cases). The apparent excess in the
Table 1. Risk factors among the patients with deep fungal infection studied at the University Surgical Clinic in Wiirzburg between November 1, 1988 and October 31, 1989
Risk factor
n
%
Operationlwound areas Antibiotic therapy Damage to intra-abdominal hollow organs Perforated/penetrating ulcer Tumour Perforation following trauma Suture insufficiency Necrosis (incarceration, rnesenteric infarction) Intensive care Central venous catheter Tracheostorny/long-term assisted respiration Parenteral feeding Bladder catheter Nasal tube Age ( > 60 years) Underweight or substantial increase in weight Malignant turnour Diabetes rnellitus Alcohol abuse Concomitant infectious disease Chemotherapy, immunosuppression, glucocorticoids, leukaernia, radiotherapy, leucopenia
42 38
100
5
90.4 73.8 21.4 16.6 14.2 11.9
4 28 28
9.5 66.6 66.6
25 25 25 7 21
59.5 59.5 59.5
12
28.5 28.5 21.4
31 9 7
6
12 9 3 3
0
16.6 50.0
7.1 7.1
0
number of organisms over the number of patients was accounted for by mixed infections. The conclusion from an analysis of the findings during the study period are that fungal infections in surgical patients are mainly found in association with damage to intra-abdominal hollow organs and that the organism are mostly present at the start of the surgical treatment. An essential question is the extent to which Candida infections occur in an intensive care ward. Twelve patients who were in our intensive care ward for more than 40 days were monitored serologically every five days. Although there were substantial fluctuations in antigen and antibody titres in all patients, none developed a clinical deep fungal infection.
Case histov
It was possible to identify the route of infection in individual patients. For example, a 56-yearold alcoholic with cirrhosis of the liver suffered a perforated gastric ulcer. H e underwent gastric resection (Billroth 11). Extensive fungal colonies were found in the necrotic tissue at the base of the ulcer in the surgical specimen. After transient insufficiency at the anastomosis, which was oversewn, small fungal granulomata were found on peritoneal biopsy. Much larger granulomata were discovered at a subsequent laparotomy. The patient developed pronounced generalized Candida peritonitis and died from Candida sepsis.
Diagnosis The diagnosis of a deep fungal infection poses a problem in that only the histological identification of an invasive growth provides the ultimate proof. Therefore, a specimen for histological examination should be taken whenever possible where a positive microbiological diagnosis has been made. For example, the histological examination of a small piece of tracheal biopsy material allows a deep fungal infection to be differentiated from the superficial fungal infection that commonly occurs in ventilated patients. Opinions on the significance of serological tests vary. Antibody tests such as the complement fixing reaction and the haemagglutination test are difficult to evaluate. Several antigen tests are currently available. Phillips and co-workers have expressed specificity of 43% [6]. I n contrast, Walsh and co-workers found the detection of circulating Candida enolase to have a sensitivity of 54% which rose to 85% after several repetitions [7]. mycoses 35, 225-228 (1992)
FUNGAL INFECTIONS IN SURGICAL PATIENTS
Treatment
Table 3. Eradication of fungus from specimen material
Since the detection of a deep fungal infection is not always possible, clinical and the subjective assessment of the treating physician play a part in making the decision to treat. However, the following are definite indications for starting antifungal treatment: ( 1) The histological detection of a deep fungal infection, (2) a positive blood culture, (3) a rising serological antibody titre and the detection of antigen, and (4)a life-threatening clinical picture. I t should also be borne in mind that all critically ill patients are prone to fungal infection and that infection can be of particular danger in these cases. The standard treatment for life-threatening fungal infection is still considered to be a combination of amphotericin B with 5-fluorocytosine [8]. However, the development of the azole antifungal agents has created new possibilities. Since fluconazole, a bis-triazole antifungal drug, is able to penetrate into all tissues and is effective against C. albicans we decided to use this agent in the treatment of our surgical patients. Between March 1 and October 31, 1988, 26 patients with deep secondary fungal infection, including 15 with peritoneal invasion, were treated with fluconazole; 22 were cured (Table 2). Colonization by Candida was totally eradicated within 12 days in more than half the patients (Table 3) [9]. Since fluconazole has only moderate activity against Candida yeasts in vitro, the monitoring of fluconazole therapy by histological examination has been studied by means of programmed peritoneal lavage [lo]. Within this study 10 patients with Candida peritonitis were treated during the period beginTable2. Mycological response to therapy at the end of treatment Principal infective focus
Patients (n)
Cured*
Peritoneum (1ocalized)t Peritoneum (generalized)$ Trachea Wound area Lungs Oesophagus Skin Necrotic retroperitoneal cavity
12
11 1 3
Total
26
3 3 3 2 1 1 1
over time Day of treatment
Cumulative percentage of microscopically and culturally negative specimens
6
27
9 12
46
15
69
18 21
81 85
54
ning May 1, 1988, to January 1, 1990. Origins of the infection were lesions and perforations of the gastrointestinal tract. The diseases were favoured by the risk factors malignancy, diabetes mellitus and extensive antibacterial chemotherapy. The mean Apache score [ 111 was 19.0. All the patients were operated on again on the grounds of a diagnosis of diffuse peritonitis and programmed peritoneal lavage was instituted. The diagnosis of Candida peritonitis was made from the microbiological findings, serological results, tissue histology (Fig. 1 ) and the clinical picture. Five of the 10 patients died from their underlying disease, even though the fungal peritonitis had been controlled. Daily laparotomy enabled histological checks to be made on the progress of the Candida peritonitis [12]. After fluconazole had been administered, the fungal elements became swollen and reduced in number within two to four days (Fig. 2).
A comparative study Since it appeared that fluconazole was able to destroy most of the invading Candida cells within 4 days (Fig. 2) a therapeutic study was undertaken in which fluconazole in a dose of 300 mg
(n)
2 2 1 1 1 22
*Cured=Five specimens taken up to four weeks after the end of treatment, negative on microscopy and culture. t Intestinal anastomosis 7; peritoneal abscess 3; drainage tube 2. $Fungal peritonitis 3.
mycoses 35, 225-228 (1992)
227
Figure 1. Viable blastospores and mycelia prior to onset of therapy with fluconazole. The peritoneum is invaded by fungi.
228
P.KUJATH
infection in surgical patients. The drug is highly effective against C. albicans, the most important fungal species pathogenic to man. Fluconazole has clear advantages over combination treatment with amphotericin B and 5-fluorocytosine on account of its good tolerability and ease of administration. Thus, the indications for prescribing an antifungal agent can be widened. Consideration must also be given to whether an antifungal agent may be given prophylactically to critically ill patients with underlying diseases such as tumours, diabetes mellitus or alcohol abuse, and particularly to patients with duodenal perforations. Four days post onset of therapy. Only foci of Cundidu blastospores markedly reduced in number with minimal mycelia can be detected; the oval blastospores exhibit hydropic changes and bullous distention. Pseudomycelia are fragmented.
Figure 2.
’
intravenously daywas compared against amphotericin B in a dose of up to 0.6 mg kg-’ body weight day- combined with 5-fluorocytosine in a dose of 2.5 g, three times a day. Patients who suffered from a deep fungal infection (as described above) were admitted to the study and randomized to treatment. Patients who did not give their consent, who were pregnant or who had previously received antifungal therapy were excluded, as were those in the terminal stages of disease. Of the 73 patients evaluated to date, 12 have been treated with the combination of amphotericin B and 5-fluorocytosine and 11 with fluconazole; all had undergone surgery and 18 had had leakage from the gastrointestinal tract. The two groups were comparable in age, height and weight. No fungi were detectable in the patients treated with amphotericin B/5-fluorocytosine after 8.3 days, and none were detectable in those treated with fluconazole after 12.2 days. Treatment had to be discontinued in one patient in the amphotericin B/5-fluorocytosine group on account of renal failure. Among the patients treated with fluconazole, the infection persisted in one case of Candidu peritonitis until the sixth day when the patient died. A clear improvement in mycological findings was otherwise evident in all patients. Six patients died, three in each group.
’
References Fegeler, W. (1983) Epidemiologie und Pathogenese generalisierender einheimischer Mykosen. Hrsg. Meinhof W., Schonfeld, H., Seeliger, H., Wegmann, T. Hahnenklee-Symposium 1982 “Systemische Mykosen”, Grenzach-Wyhlen, Roche, 19. Newman, F. & Rakower, S. (1978) The risk of positive cultures for Cundidu in the critically ill patient. Crif. Cure Med. 6 , 73-76. Solomkin, J., Flohr, A. & Simmons, R. (1982) Cundida infections in surgical patients. Ann. Surg. 195, 172-185. Young, R., Bennet, J., Geelhoed, G. cf ul. (1974) Fungemia with compromised host resistance. A study of 70 cases. Ann. Intern. Med. 80, 605-612. Graybill, J. R. & Sharkey, P. K. (1990) Fungal infections and their management. Br. J . Clin. Prucf. 44 (suppl 71), 23-3 1. Phillips, P., Dowd, A., Jewesson, P. el ul. (1990) Nonvalue of antigen detection immunoassays for diagnosis of candidemia. J. Clin. Microbiol. 28, 2320-2326. Walsh, T. J., Hathorn, J., Sobel, J. D. ef ul. (1991) Detection of circulating Cundidu enolase by immunoassay in patients with cancer and invasive candidiasis. N. Engl. J. Med. 324, 1026-1031. Perfect, J. R. (1991) Antifungal therapy and its use in surgical treatment. Surg. Cynec. Obsfef.171, 41-48. Kujath, P. & Lerch, K. (1989) New antimicrobial agents under clinical investigation: secondary mycosis in surgerv: treatment with fluconazole. Infecfion17. 56-63. 10 k e i n , E., Klaue, P. & Arbogast, R. (1983) Programmierte Peritoneallavage bei diffuser Peritonitis. Chirurg 54: 306-310. 1 1 Knaus, W. A., Zimmermann, J. E., Wagner, D. P., Draper, E. & Lawrence, D. Apache-acute physiology and chronic health evaluation: a physiologically based classification system. Crif. Care Med. 9, 591-597. 12 Kujath, P., Lerch, K. & Dammrich, J. (1990) Fluconazole monitoring in Cundidu peritonitis based in histological control. Mycoses 33, 441-448.
Conclusion The introduction of fluconazole has opened up new possibilities in the treatment of deep fungal
mycoses 35, 225-228 (1992)
