Brief Communications/Kurzmitteiiungen Sir,
The emergence of Candida albicans resistant to miconazole during the treatment of urinary tract candidosis The antifungal imidazole derivative clotrimazole (Bayer) came under laboratory investigation here in mid-1969, and soon after this it was used orally for the treatment of systemic candidoses in infants in this hospital (1, 2). Within a year a second derivative, miconazole, and, considerably later, a third, econazole (both by Janssen), were similarly studied. Since 1969 over 1000 individual clinical isolates of Candida species have been tested for sensitivity to these drugs by the disc and liquid dilution methods detailed later (3); until very recently no 'wild' isoIate with resistance to these drugs had been found, nor had repeated in vitro and cllnical studies revealed any strain with significantly increased resistance after even prolonged exposure to these drugs. We report below our first experience of emergent resistance to miconazole of Candida albieans during prolonged therapy for urinary candidosis; the strain showed equally increased resistance to clotrimazote and econazole. A new born male infant was admitted to this hospital on the 20th April 1977 under the care of Mr. H. B. Eckstein, consultant paediatric surgeon. I n addition to a high anorectal agenesis, he was found to have bilateral hydronephrosis with bilateral ureteric reflux and recto-urethral fistula; a right transverse colostomy was done immediately. F r o m the first week his urinary tract was heavily infected by a sequence of bacteria, including Pseudomonas aeruginosa and Escherichia coli and nitrofurantoin, co-trimoxazole, ampicillin and gentamicin were given at various times. On 23rd May, vesicostomy was done to reduce the outflow resistance as a temporary measure for the relief of the ureteric reflux and to ensure prompt change of bladder contents. Soon after this C. aIbicans appeared in urine cultures, and was initially sensitive to 5-flu0rocytosine (5FC), the three imidazoles and amphotericin B (Table 1). Intravenous 5FC was given for one week at 25 mg per kg body wt. each 12 hours, followed by five weeks oral 5FC at 100 m/kg/day given 6 hourly in suspension form by naso-gastric tube. Serum and urine assays gave 5FC levels up to 90 mg/t and 500 mg/l respectively. After the first Table 1: Changes in the minimal inhibitory and cidal concentration (MIC and MCC) for isolates of C. albicans. Antifungal drug mg/1
DATE 5FC
Miconazole
Econazole
Clotrimazole
Amphotericin B 0.05
30th May M I C 0.05
0.2
0.2
0.2
M C C 0.1
0.5
0.5
0.5
13 July
30 Oct.
19 Nov.
198
M I C 1000
0.2
0.2
0.2
MCC 1000
0.5
0.5
0.5
M I C 1000
2
2
2
MCC 1000
10-20
10
10-20
M I C 1000
20
10-20
20
MCC 1000
100
100
100
Infection 6 (1978) Nr. 4
0.05
week no Candida was cultured in daily urine samples, but during the sixth week C. aIbicans reappeared, now virtually resistant to 5FC by disc and liquid tests. The strain appeared to be identical in all other respect to the original isolates. On the 11th August the vesicostomy was closed, together with abdominoperineal rectal pull-through and ligation and division of the recto-urethral fistula. C. albicans continued in the urine, and because further surgery was planned for late September, oral miconazole was started on 19th September at a dose of 100 mg/kg/day at 6-hourly intervals. It was given by naso-gastric tube as a suspension prepared by diluting an oral gel kindly supplied by Mr. Barton of Janssen with glucose saline so that each dose totaled 10 ml. Nephrostomy was performed on 29th September, drain tubes for both ureter and the bladder were kept in situ for 16 days. During this time 10 ml volumes of a 0.1°/0 suspension of miconazole in saline were instilled into the nephrostomy drain twice daily, retained in the tube for 1 hour and then released. During this period the Candida count in daily urine samples gradually dropped until, by mid October, no Candida was cultured from repeated specimens; serum assays recorded levels of miconazole up to 1.1 nag/l, urine levels up to 1 mg/l and the faeces contained about 100 #g/g wet weight. Drain tubes were removed on 26th October, and soon after this C. albicans reappeared in the urine; the isolate of 30th October required an minimal inhibitory concentration (MIC) of 2 rag/1 and was still totally resistant to 5FC. Oral micoazole was continued until 18th November, by which time each daily urine yielded a profuse growth of C. albicans, now requiring an M I C of 20 mgfl. Miconazole therapy was therefore discontinued. The last isolates appeared identical in all other respects to those recovered earlier. By this time the infant was in good clinical condition, despite the heavy urinary tract infection; a considerable increase in fluid intake had little effect in clearing the infection, so it was decided to give potassium citrate mixture by mouth. The urinary pH soon rose from below 6.0 to between 8.0 and 8.5, and the Candida colony count dropped rapidly to below 1 x 10"- viable units/ml, although P. aeruginosa reappeared in the urine. Experience during the past thirty years of the changing patterns of sensitivity of many micro-organisms to antimicrobial drugs, particularly the recent alarming reports of pneumococci relatively resistant to benzylpenicillin, has led the older and more pessimistic of us to anticipate the eventual appearance of fungi of clinical interest with increased or total resistant to the newer antifungal drugs. Shadomy (4) soon found several examples of 'wild' and emergent resistance to 5FC, and his observations have been repeated by workers in m a n y parts of the world. Now an imidazole-resistant candida specie has emerged resistant to all three available antifungal derivatives; at this m o m e n t it is impossible to predict whether this be a rare event or whether it heralds increasing numbers of such strains. It must be stressed that this observation in no way lessens the immense value of the antifungaI imidazoles, or for that matter 5FC, but it does mean that extreme vigilance must be maintained in laboratories concerned with in vitro sensitivity tests with antimycotic agents and particularly by those who monitor the progress of patients receiving these drugs for topical and systemic infections.
Literature 1. Holt, R. J., Newman, R. L.: Laboratory assessment of the antimycotic drug clotrimazote, J. Clin. Pathol. 25 (1972) 1089-1097. 2. Holt, R. or., Newman, R. L.: The treatment of urinary candidosis with the oral antifungal drugs 5-fluorocytosine and clotrimazole. Dev. Med. Child Neurol. Suppl. 70 (1973) 7079. 3. Holt, R. or.: Laboratory tests of antifungal drugs. J. Clin. Pathol. 28 (1975) 767-774.
Paul-Ehrlich-Gesellschaftfiir Chemotherapie Am 22. September :1978 findet die diesjiihrige wissenschaffliche Arbeitstagnng in Frankfurt am Main (GroBer H6rsaal, Zentralgebiiude des Ktinikums) start. Hauptthema dieser Arbeitstagung: ,,Antibiotika-inaktivierende Enzyme". Als Referenten sind vorgesehen: Richmond, M., Bristol, UK ,,Beta-Lactamases - a mechanism of bacterial resistance to Beta-lactam-antibiotics" Zimmermann, W., Basel ,,Penetration durch die bakterielle Zellhfille: ein mithestim-
4. Shadomy, S.: in vitro studies with 5-fluorocytoslne. Appl. Microbiol. 17 (1969) 871-877. R. I. Holt, MRC Path., PhD A. Azmi, FRCS Queen Mary's Hospital for Children Carshalton, Surrey, SM5 4NR United Kingdom Editors Footnote: Although a shortened version of this letter has already appeared in another journal, we are printing the letter here at the author's request and because we are aware of the importance of the contents.
mender Faktor ftir die Wirksamkeit yon Beta-Lactam-Antibiotika"
Davies, or., Madison, Wisconsin ,,Transferases - mechanism of bacterial resistance to aminoglycoside-antibiotics" Wiedemann, B , Bonn ,,Die Ausbreitung yon Aminoglycosid-Transferasen bei gramnegativen Bakterien". Augerdem sind zu dem genannten Hauptthema zwei Rundtisch-Gespr~iche vorgesehen, die die ResistenzverNiltnisse aus mikrobiologischer und aus klinischer Sicht behandeln.
Book Reviews / Buchbesprechungen Th. Luthardt:
Cytomegalie 56 Seiten, 4 Abbildungen Enke Verlag, Stuttgart, 1976 Preis: D M 29,70 Das Cytomegalie-Virus ist wettweit verbreitet und fiihrt schon im frfihen Kindesalter zu einer hohen Durchseuchung. Die durch das Cytomegalie-Virus hervorgerufenen Krankheitsbilder sind vielseitig und beriihren die Arbeitsgebiete des P~idiaters, des Internisten, des Onkologen und des praktischen Arztes. Aus diesem Grund kann man das Erscheinen einer iibersichtlichen Arbeit tiber die Cytomegalie nur begrfigen. Bisher fehlte eine deutschsprachige Zusammenstellung mit Berficksidatigung der neuesten Literatur. Der Verfasser des Buches ist sowohl Piidiater als auch Virologe und hat auf dem Gebiet der Cytomegalie wichtige Untersuchungen durchgefiihrt. Es ist selbstversfiindlich, dab diese seine reichhaltige Erfahrung ihren Niederschlag in dem vorliegenden Buch findet. Dadurch wird das Buch besonders wertvoll. Jeder der angesprochenen .~rzte hat die MSglichkeit sich fiber die Erkrankungen, die durch das Cytomegatie-Virus hervorgernfen werden, schnell zu orientieren. Ganz im Vordergrund stehen die angeborene intrauterin erworbene Infektion. Man findet auch eine eingehende Schilderung der epidemiologischen Besonderheiten der Cytomegalie-Virusinfektion. Auch die diagnostischen M6glichkeiten werden ausftihrlich dargestellt. Der virologische tiitige Arzt findet viele praktische Hinweise. Bedenkt man, dab eine pr~inatale Cytomegalieinfektion bei 1%. alter Siiuglinge anftritt und yon diesen infizierten Kindern 10-159/0 klinische Symptome mehr oder weniger schwerer Art aufweisen, dab weiterhin jeder vierte bis ffinfte Siiugling eine perioder postnatale Infektion anfweist, die unter Umst~inden zu cerebralen Sch~idignngen ffihren kann und bedenkt man wei-
terhin, dab die Cytomegalie bei Organtransplantation eine geftirchtete Komplikation darstellt, so wird die Bedeutung dieser ausgezeichneten Arbeit ersichtlich. Ein gut ansgewiihltes Literaturverzeichnis erhSht den Wert des Buches.
O. Goetz, Universifiits-Kinderklinik, Mfinchen L. Jiiger:
Klinische Immunologic und Allergologie (In zwei Teilen) 1091 Seiten, 196 Abbildungen, 110 Tabellen Gustav Fischer Verlag, Stuttgart 1976 Preis: D M 148,-Dieses handbuchartig umfangreiche Immunologie-Buch soil dem Kliniker immunologisch-diagnostische Methoden, Erkenntnisse tiber immunologisch bedingte Erkrankungen und den Einsatz immunologischer Behandlungsarten niiherbringen. Diese schwierige Aufgabe ist ein einzelner Autor angegangen und hat sie Kapitel ftir Kapitel gemeistert. Die Grundlagen, die diagnostischen Methoden, wie auch die experimentelle und klinische Immunpathologie sind praktisch liickenlos abgehandelt. Um so bedauerlicher, dab der Autor in einigen entscheidenden Ausstattungen des doppelbiindigen Werkes yon seinem Herausgeber im Stich gelassen wurde" 1. Literaturangaben, wenn sie sich auch schon auf Bticher, Monographien und t3bersichtsarbeiten beschr~inken mugten, sollten nach jedem Kapitel erscheinen. 2. Die Literaturzitate im Text sind ausgesprochen unbefriedigend, so ist z. B. Tabelle 4e in Kapitel 1 bei J. F. Bach entliehen, Abbildungen 9-10 Craddock's Arbeiten entnommen, aber beide Autoren sind im Literaturverzeichnis ffir diese Referenzen unauffindbar.
Infection 6 (1978) Nr. 4
199
The emergence of Candida albicans resistant to miconazole during the treatment of urinary tract candidosis The antifungal imidazole derivative clotrimazole (Bayer) came under laboratory investigation here in mid-1969, and soon after this it was used orally for the treatment of systemic candidoses in infants in this hospital (1, 2). Within a year a second derivative, miconazole, and, considerably later, a third, econazole (both by Janssen), were similarly studied. Since 1969 over 1000 individual clinical isolates of Candida species have been tested for sensitivity to these drugs by the disc and liquid dilution methods detailed later (3); until very recently no 'wild' isoIate with resistance to these drugs had been found, nor had repeated in vitro and cllnical studies revealed any strain with significantly increased resistance after even prolonged exposure to these drugs. We report below our first experience of emergent resistance to miconazole of Candida albieans during prolonged therapy for urinary candidosis; the strain showed equally increased resistance to clotrimazote and econazole. A new born male infant was admitted to this hospital on the 20th April 1977 under the care of Mr. H. B. Eckstein, consultant paediatric surgeon. I n addition to a high anorectal agenesis, he was found to have bilateral hydronephrosis with bilateral ureteric reflux and recto-urethral fistula; a right transverse colostomy was done immediately. F r o m the first week his urinary tract was heavily infected by a sequence of bacteria, including Pseudomonas aeruginosa and Escherichia coli and nitrofurantoin, co-trimoxazole, ampicillin and gentamicin were given at various times. On 23rd May, vesicostomy was done to reduce the outflow resistance as a temporary measure for the relief of the ureteric reflux and to ensure prompt change of bladder contents. Soon after this C. aIbicans appeared in urine cultures, and was initially sensitive to 5-flu0rocytosine (5FC), the three imidazoles and amphotericin B (Table 1). Intravenous 5FC was given for one week at 25 mg per kg body wt. each 12 hours, followed by five weeks oral 5FC at 100 m/kg/day given 6 hourly in suspension form by naso-gastric tube. Serum and urine assays gave 5FC levels up to 90 mg/t and 500 mg/l respectively. After the first Table 1: Changes in the minimal inhibitory and cidal concentration (MIC and MCC) for isolates of C. albicans. Antifungal drug mg/1
DATE 5FC
Miconazole
Econazole
Clotrimazole
Amphotericin B 0.05
30th May M I C 0.05
0.2
0.2
0.2
M C C 0.1
0.5
0.5
0.5
13 July
30 Oct.
19 Nov.
198
M I C 1000
0.2
0.2
0.2
MCC 1000
0.5
0.5
0.5
M I C 1000
2
2
2
MCC 1000
10-20
10
10-20
M I C 1000
20
10-20
20
MCC 1000
100
100
100
Infection 6 (1978) Nr. 4
0.05
week no Candida was cultured in daily urine samples, but during the sixth week C. aIbicans reappeared, now virtually resistant to 5FC by disc and liquid tests. The strain appeared to be identical in all other respect to the original isolates. On the 11th August the vesicostomy was closed, together with abdominoperineal rectal pull-through and ligation and division of the recto-urethral fistula. C. albicans continued in the urine, and because further surgery was planned for late September, oral miconazole was started on 19th September at a dose of 100 mg/kg/day at 6-hourly intervals. It was given by naso-gastric tube as a suspension prepared by diluting an oral gel kindly supplied by Mr. Barton of Janssen with glucose saline so that each dose totaled 10 ml. Nephrostomy was performed on 29th September, drain tubes for both ureter and the bladder were kept in situ for 16 days. During this time 10 ml volumes of a 0.1°/0 suspension of miconazole in saline were instilled into the nephrostomy drain twice daily, retained in the tube for 1 hour and then released. During this period the Candida count in daily urine samples gradually dropped until, by mid October, no Candida was cultured from repeated specimens; serum assays recorded levels of miconazole up to 1.1 nag/l, urine levels up to 1 mg/l and the faeces contained about 100 #g/g wet weight. Drain tubes were removed on 26th October, and soon after this C. albicans reappeared in the urine; the isolate of 30th October required an minimal inhibitory concentration (MIC) of 2 rag/1 and was still totally resistant to 5FC. Oral micoazole was continued until 18th November, by which time each daily urine yielded a profuse growth of C. albicans, now requiring an M I C of 20 mgfl. Miconazole therapy was therefore discontinued. The last isolates appeared identical in all other respects to those recovered earlier. By this time the infant was in good clinical condition, despite the heavy urinary tract infection; a considerable increase in fluid intake had little effect in clearing the infection, so it was decided to give potassium citrate mixture by mouth. The urinary pH soon rose from below 6.0 to between 8.0 and 8.5, and the Candida colony count dropped rapidly to below 1 x 10"- viable units/ml, although P. aeruginosa reappeared in the urine. Experience during the past thirty years of the changing patterns of sensitivity of many micro-organisms to antimicrobial drugs, particularly the recent alarming reports of pneumococci relatively resistant to benzylpenicillin, has led the older and more pessimistic of us to anticipate the eventual appearance of fungi of clinical interest with increased or total resistant to the newer antifungal drugs. Shadomy (4) soon found several examples of 'wild' and emergent resistance to 5FC, and his observations have been repeated by workers in m a n y parts of the world. Now an imidazole-resistant candida specie has emerged resistant to all three available antifungal derivatives; at this m o m e n t it is impossible to predict whether this be a rare event or whether it heralds increasing numbers of such strains. It must be stressed that this observation in no way lessens the immense value of the antifungaI imidazoles, or for that matter 5FC, but it does mean that extreme vigilance must be maintained in laboratories concerned with in vitro sensitivity tests with antimycotic agents and particularly by those who monitor the progress of patients receiving these drugs for topical and systemic infections.
Literature 1. Holt, R. J., Newman, R. L.: Laboratory assessment of the antimycotic drug clotrimazote, J. Clin. Pathol. 25 (1972) 1089-1097. 2. Holt, R. or., Newman, R. L.: The treatment of urinary candidosis with the oral antifungal drugs 5-fluorocytosine and clotrimazole. Dev. Med. Child Neurol. Suppl. 70 (1973) 7079. 3. Holt, R. or.: Laboratory tests of antifungal drugs. J. Clin. Pathol. 28 (1975) 767-774.
Paul-Ehrlich-Gesellschaftfiir Chemotherapie Am 22. September :1978 findet die diesjiihrige wissenschaffliche Arbeitstagnng in Frankfurt am Main (GroBer H6rsaal, Zentralgebiiude des Ktinikums) start. Hauptthema dieser Arbeitstagung: ,,Antibiotika-inaktivierende Enzyme". Als Referenten sind vorgesehen: Richmond, M., Bristol, UK ,,Beta-Lactamases - a mechanism of bacterial resistance to Beta-lactam-antibiotics" Zimmermann, W., Basel ,,Penetration durch die bakterielle Zellhfille: ein mithestim-
4. Shadomy, S.: in vitro studies with 5-fluorocytoslne. Appl. Microbiol. 17 (1969) 871-877. R. I. Holt, MRC Path., PhD A. Azmi, FRCS Queen Mary's Hospital for Children Carshalton, Surrey, SM5 4NR United Kingdom Editors Footnote: Although a shortened version of this letter has already appeared in another journal, we are printing the letter here at the author's request and because we are aware of the importance of the contents.
mender Faktor ftir die Wirksamkeit yon Beta-Lactam-Antibiotika"
Davies, or., Madison, Wisconsin ,,Transferases - mechanism of bacterial resistance to aminoglycoside-antibiotics" Wiedemann, B , Bonn ,,Die Ausbreitung yon Aminoglycosid-Transferasen bei gramnegativen Bakterien". Augerdem sind zu dem genannten Hauptthema zwei Rundtisch-Gespr~iche vorgesehen, die die ResistenzverNiltnisse aus mikrobiologischer und aus klinischer Sicht behandeln.
Book Reviews / Buchbesprechungen Th. Luthardt:
Cytomegalie 56 Seiten, 4 Abbildungen Enke Verlag, Stuttgart, 1976 Preis: D M 29,70 Das Cytomegalie-Virus ist wettweit verbreitet und fiihrt schon im frfihen Kindesalter zu einer hohen Durchseuchung. Die durch das Cytomegalie-Virus hervorgerufenen Krankheitsbilder sind vielseitig und beriihren die Arbeitsgebiete des P~idiaters, des Internisten, des Onkologen und des praktischen Arztes. Aus diesem Grund kann man das Erscheinen einer iibersichtlichen Arbeit tiber die Cytomegalie nur begrfigen. Bisher fehlte eine deutschsprachige Zusammenstellung mit Berficksidatigung der neuesten Literatur. Der Verfasser des Buches ist sowohl Piidiater als auch Virologe und hat auf dem Gebiet der Cytomegalie wichtige Untersuchungen durchgefiihrt. Es ist selbstversfiindlich, dab diese seine reichhaltige Erfahrung ihren Niederschlag in dem vorliegenden Buch findet. Dadurch wird das Buch besonders wertvoll. Jeder der angesprochenen .~rzte hat die MSglichkeit sich fiber die Erkrankungen, die durch das Cytomegatie-Virus hervorgernfen werden, schnell zu orientieren. Ganz im Vordergrund stehen die angeborene intrauterin erworbene Infektion. Man findet auch eine eingehende Schilderung der epidemiologischen Besonderheiten der Cytomegalie-Virusinfektion. Auch die diagnostischen M6glichkeiten werden ausftihrlich dargestellt. Der virologische tiitige Arzt findet viele praktische Hinweise. Bedenkt man, dab eine pr~inatale Cytomegalieinfektion bei 1%. alter Siiuglinge anftritt und yon diesen infizierten Kindern 10-159/0 klinische Symptome mehr oder weniger schwerer Art aufweisen, dab weiterhin jeder vierte bis ffinfte Siiugling eine perioder postnatale Infektion anfweist, die unter Umst~inden zu cerebralen Sch~idignngen ffihren kann und bedenkt man wei-
terhin, dab die Cytomegalie bei Organtransplantation eine geftirchtete Komplikation darstellt, so wird die Bedeutung dieser ausgezeichneten Arbeit ersichtlich. Ein gut ansgewiihltes Literaturverzeichnis erhSht den Wert des Buches.
O. Goetz, Universifiits-Kinderklinik, Mfinchen L. Jiiger:
Klinische Immunologic und Allergologie (In zwei Teilen) 1091 Seiten, 196 Abbildungen, 110 Tabellen Gustav Fischer Verlag, Stuttgart 1976 Preis: D M 148,-Dieses handbuchartig umfangreiche Immunologie-Buch soil dem Kliniker immunologisch-diagnostische Methoden, Erkenntnisse tiber immunologisch bedingte Erkrankungen und den Einsatz immunologischer Behandlungsarten niiherbringen. Diese schwierige Aufgabe ist ein einzelner Autor angegangen und hat sie Kapitel ftir Kapitel gemeistert. Die Grundlagen, die diagnostischen Methoden, wie auch die experimentelle und klinische Immunpathologie sind praktisch liickenlos abgehandelt. Um so bedauerlicher, dab der Autor in einigen entscheidenden Ausstattungen des doppelbiindigen Werkes yon seinem Herausgeber im Stich gelassen wurde" 1. Literaturangaben, wenn sie sich auch schon auf Bticher, Monographien und t3bersichtsarbeiten beschr~inken mugten, sollten nach jedem Kapitel erscheinen. 2. Die Literaturzitate im Text sind ausgesprochen unbefriedigend, so ist z. B. Tabelle 4e in Kapitel 1 bei J. F. Bach entliehen, Abbildungen 9-10 Craddock's Arbeiten entnommen, aber beide Autoren sind im Literaturverzeichnis ffir diese Referenzen unauffindbar.
Infection 6 (1978) Nr. 4
199
