Correspondence
1196
Nicholas J. White, Sanjeev Krishna, and Sornchai Looareesuwan Nuffield Department of Clinical Medicine. John Radcliffe Hospital. Oxford University. United Kingdom; Bangkok Hospital for Tropical Diseases. Faculty of Tropical Medicine. Mahidol University. Thailand
Reply
Reference I. Chia JKS. Nakata MM, Co S. Smear-negative cerebral malaria due to mefloquine-resistant Plasmodium falciparum acquired in the Amazon [letter]. J Infect Dis 1992;165:599-600.
We agree with White et al. that the diagnosis of cerebral malaria should usually be based on positive findings. We speculate that the delayed onset of cerebral symptoms after clearance of peripheral parasitemia. a feature thought to be inconsistent with cerebral malaria according to the experience of White et al., may be partly explained by the much longer serum half-life of mefloquine (unlike chloroquine-the drug often used for treatment in prior reports of cerebral malaria) in combination with the modest antimalarial effects of doxycycline and ciprofloxacin, which were administered from first admission to onset of cerebral symptoms. The patient's neurologic examination at 3-month follow-up was completely normal. We still suspect this case is a rare example of cerebral malaria with manifestations modified by a number of drugs with different antimalarial properties. John K. S. Chia and Michael M. Nakata Private Practice. Harbor City. California References
Reprints or correspondence: Dr. John K. S. Chiao 1403 W. Lomita Blvd., Suite 20 I, Harbor City. CA 90710. The Journal of Infectious Diseases 1992;166:1196 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0045$01.00
Amphotericin B-Resistant Candida albicans To the Editor-Conly et al. [ J recently published an article that has several inherent problems. They make recommendations that "patients with bloodstream infections with Candida albicans should be monitored for the presence of possible resistance." They further state that such tests "also allow the selection of the most potent combination therapy for an individual patient." This is based on the results obtained from poorly designed susceptibility tests done on 7 isolates from a single patient. Articles such as this create inappropriate requests for clinical microbiology laboratories to perform such tests routinely. The specific concerns I have relative to their article are as follows:
Reprints or correspondence: Dr. Roy L. Hopfer. Department of Clinical Microbiology-Immunology. CB 7600. University of North Carolina Hospitals. Chapel Hill. NC 27514. The Journal of Infectious Diseases 1992;166:1196-7 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0046$01.00
I. White NJ, Krishna S. Looareesuwan S. Encephalitis. not cerebral malaria, is likely cause of coma with negative blood smears [letter]. J Infect Dis 1992; 166: 1195-6. 2. Chia JKS. Nakata MM. Co S. Smear-negative cerebral malaria due to mefloquine-resistant Plasmodium [alciparum acquired in the Amazon [letter]. J Infect Dis 1992; 165:599-600.
First, as the authors show, MICs of amphotericin B can reliably be determined in Sabouraud dextrose broth at pH 5.6. However, it has been known since the early 1970s that pyrimidinefree medium must be used when determining MICs of 5-fluorocytosine [2]. Unfortunately, Sabouraud broth contains peptones, may not be pyrimidine-free, and may give falsely elevated 5-fluorocytosine MICs. This makes interpretation of the authors' synergy studies questionable at best. Second, regardless of the actual MICs, the data presented in table 2 indicate that levels of amphotericin B as low as 0.31 mg/L have a demonstrable effect on the isolate when tested with 5-fluorocytosine. That is, 0.31 mg/L presumably causes changes in the cell surface sufficient to allow increased entry of 5-fluorocytosine into the cell. Therefore, even though the isolates are resistant to amphotericin B (MIC = 2.5 mg/L), the drug still has a damaging effect on the cell surface at a much lower (clinically achievable) concentration (0.31 mg/L). Third, according to table I, the MICs of both amphotericin B and miconazole are 2.5 mg/L. However, in table 2 at this same concentration of drug, 0.08 and 10 mg of 5-fluorocytosine/mL are required to inhibit growth in the presence ofamphotericin B and miconazole, respectively.
Downloaded from http://jid.oxfordjournals.org/ at UQ Library on June 20, 2015
To the Editor-We appreciate the constructive comments by White et al. [I], who have extensive experience with cerebral malaria and other tropical infectious diseases. We agree that the diagnosis of cerebral malaria is only probable based on the evidence provided in our case [2]. We considered common causes of viral encephalitis, and these were excluded by negative serology. A possible coexisting infection due to one of the unusual arboviruses could not be excluded without more refined serologic tests. However, the dramatic clinical improvement after initiation of quinine and doxycycline therapy in a persistently febrile patient with sudden, rapidly deteriorating mental status supports the diagnosis of cerebral malaria. Furthermore, this therapeutic response and a rapid defervescence after antimalarial treatment are also inconsistent with the diagnoses of viral or postinfectious encephalitides.
lID 1992; 166 (November)
JIO 1992: 166 (November)
Correspondence
Reply To the Editor-Hopfer [I] raises several questions that deserve comment. We disagree that the results obtained were from poorly designed susceptibility tests and that our article will create inappropriate requests for clinical microbiology laboratories to do routine antifungal susceptibility testing. Specific concerns have been raised with regard to the methods used in our study [2] for the antifungal susceptibility testing. Although it was not reported in that article, a review of other experimental data (unpublished data) revealed that the strains tested had the same MICs on antibiotic medium no. 3 at neutral pH, and there are other data with other strains of Candida albicans tested against 5-fluorocytosine in Sabouraud dextrose broth that show a significant range of MICs of this drug. These data suggest that in our hands, there is a range ofMICs of 5-fluorocytosine that is not appreciably affected by the possible presence of any pyrimidine in the Sabouraud dextrose broth. Furthermore, the reduction in MICs that we saw with the addition of both drugs would argue against a falsely elevated MIC of 5-fluorocytosine. These observations suggest that our synergy studies appropriately reflect the interaction between amphotericin Band 5-fluorocytosine that we observed. With the use of appropriate controls, replicate assays, and standardized inoculum to avoid variability in our results, we have no reason to believe the assays were poorly designed. . Regarding the interpretation of table 2, it does not suggest that it required 0.08 and 10 mg/L 5-fluorocytosine to inhibit the growth of organisms in the presence of, respectively, amphotericin Band miconazole but that at higher concentrations of amphotericin B or miconazole, the cells are disrupted sufficiently to allow increased concentrations of 5-fluorocytosine to enter the cell, thus requiring less of the drug to inhibit growth ofthe organ-
Reprints or correspondence: Dr. J. Conly. Division of Infectious Diseases. Department of Medicine. Royal University Hospital. Saskatoon. Canada S7N OXO. The Journal of Infectious Diseases 1992;166:1197-8 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0047$01.00
In conclusion, incidental findings based on poorly designed laboratory assays done on isolates from one patient hardly seem sufficient to imply recommendations for routine susceptibility testing of blood stream isolates of C. albicans. Roy L. Hopfer Department of Clinical Microbiology-Immunology, University ofNorth Carolina Hospitals, Chapel Hill References I. Conly J. Rennie R. Johnson J, Farah S, Hellman L. Disseminated candidiasis due to amphotericin B-resistant Candida albicans. J Infect Dis 1992; I 65:761-4. 2. Polak A, Scholer HJ. Fungistatic activity. uptake and incorporation of 5-fluorocysine in Candida albicans as influenced by pyrimidines and purines. I. Reversal to experiments. Pathol Microbiol 1973;39:
148-59.
ism. All MIC data were presented in SI units (Ie Systeme International d'Unites) [3]. Pertinent clinical observations were made in our article. The presence of persistently positive blood cultures for C. albicans despite an adequate dose and duration of treatment with amphotericin B and in a patient in whom no focal undrained collection can be found should arouse the suspicion ofresistance to amphotericin B. This clinical setting is not common, and we are certainly not recommending routine antifungal susceptibility testing in every patient who has candidernia, but susceptibility testing in the clinical setting we described would be quite justified and arguably good medical care and optimal use of laboratory services. Rather than "making a giant leap of faith," we merely presented an observation between an in vitro phenomenon with the reduction in the MIC of amphotericin B after the addition of 5-fluorocytosine with sterilization of blood cultures after addition of 5-fluorocytosine to the patient's therapeutic regimen. Although it was not stated in the paper, he had received a total of 400 mg of amphotericin B without having one negative blood culture and had not defervesced. Although it is possible that the addition of 5-fluorocytosine was coincidental to the cultures becoming negative, we think that this is very unlikely. After 5-fluorocytosine was added to the therapeutic regimen, there was defervescence, sterilization of blood cultures. improved clinical well being, and, even though the patient died, no evidence of viable C. albicans on extensive postmortem examination. We would be cautious to say that this does not imply cause and effect; stating that there is an association between the in vitro and in vivo observations is justified. There are now convincing data that have demonstrated a correlation between in vitro fungal susceptibility and the in vivo effect of antifungal agents [4, 5]. Furthermore, the combination of amphotericin Band 5-fluorocytosine has been shown to be more effective than either agent alone in vitro against many species of Candida [6].
J. Conly and R. Rennie Division of lnfectious Diseases, Department of Medicine. Royal University Hospital. Saskatoon. and Department of Microbiology. University ofAlberta Hospitals, Edmonton, Canada
Downloaded from http://jid.oxfordjournals.org/ at UQ Library on June 20, 2015
Fourth, unfortunately, there is no control in this single patient to determine outcome if 5-fluorocytosine were not given. The authors admit "there are no data to indicate there may be a better therapeutic outcome with the combination of 5-fluorocytosine and amphotericin B." They then make a giant leap of faith stating that their "results showed a significant reduction in the MIC of amphotericin B after addition of 5-fluorocytosine, which was associated with sterilization of blood cultures and a clinical benefit to the patient." In all likelihood, in a relatively intact immune setting, such "sterilization" would have happened with amphotericin B alone. One could argue that the addition of 5-fluorocytosine was coincidental to, not the cause of, cultures becoming negative. Even if their in vitro data are correct, 5-fluorocytosine did not cause a significant reduction in the MIC of amphotericin B, but rather the combination allowed use of lower concentrations of both drugs to attain the same in vitro effect.
1197
1196
Nicholas J. White, Sanjeev Krishna, and Sornchai Looareesuwan Nuffield Department of Clinical Medicine. John Radcliffe Hospital. Oxford University. United Kingdom; Bangkok Hospital for Tropical Diseases. Faculty of Tropical Medicine. Mahidol University. Thailand
Reply
Reference I. Chia JKS. Nakata MM, Co S. Smear-negative cerebral malaria due to mefloquine-resistant Plasmodium falciparum acquired in the Amazon [letter]. J Infect Dis 1992;165:599-600.
We agree with White et al. that the diagnosis of cerebral malaria should usually be based on positive findings. We speculate that the delayed onset of cerebral symptoms after clearance of peripheral parasitemia. a feature thought to be inconsistent with cerebral malaria according to the experience of White et al., may be partly explained by the much longer serum half-life of mefloquine (unlike chloroquine-the drug often used for treatment in prior reports of cerebral malaria) in combination with the modest antimalarial effects of doxycycline and ciprofloxacin, which were administered from first admission to onset of cerebral symptoms. The patient's neurologic examination at 3-month follow-up was completely normal. We still suspect this case is a rare example of cerebral malaria with manifestations modified by a number of drugs with different antimalarial properties. John K. S. Chia and Michael M. Nakata Private Practice. Harbor City. California References
Reprints or correspondence: Dr. John K. S. Chiao 1403 W. Lomita Blvd., Suite 20 I, Harbor City. CA 90710. The Journal of Infectious Diseases 1992;166:1196 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0045$01.00
Amphotericin B-Resistant Candida albicans To the Editor-Conly et al. [ J recently published an article that has several inherent problems. They make recommendations that "patients with bloodstream infections with Candida albicans should be monitored for the presence of possible resistance." They further state that such tests "also allow the selection of the most potent combination therapy for an individual patient." This is based on the results obtained from poorly designed susceptibility tests done on 7 isolates from a single patient. Articles such as this create inappropriate requests for clinical microbiology laboratories to perform such tests routinely. The specific concerns I have relative to their article are as follows:
Reprints or correspondence: Dr. Roy L. Hopfer. Department of Clinical Microbiology-Immunology. CB 7600. University of North Carolina Hospitals. Chapel Hill. NC 27514. The Journal of Infectious Diseases 1992;166:1196-7 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0046$01.00
I. White NJ, Krishna S. Looareesuwan S. Encephalitis. not cerebral malaria, is likely cause of coma with negative blood smears [letter]. J Infect Dis 1992; 166: 1195-6. 2. Chia JKS. Nakata MM. Co S. Smear-negative cerebral malaria due to mefloquine-resistant Plasmodium [alciparum acquired in the Amazon [letter]. J Infect Dis 1992; 165:599-600.
First, as the authors show, MICs of amphotericin B can reliably be determined in Sabouraud dextrose broth at pH 5.6. However, it has been known since the early 1970s that pyrimidinefree medium must be used when determining MICs of 5-fluorocytosine [2]. Unfortunately, Sabouraud broth contains peptones, may not be pyrimidine-free, and may give falsely elevated 5-fluorocytosine MICs. This makes interpretation of the authors' synergy studies questionable at best. Second, regardless of the actual MICs, the data presented in table 2 indicate that levels of amphotericin B as low as 0.31 mg/L have a demonstrable effect on the isolate when tested with 5-fluorocytosine. That is, 0.31 mg/L presumably causes changes in the cell surface sufficient to allow increased entry of 5-fluorocytosine into the cell. Therefore, even though the isolates are resistant to amphotericin B (MIC = 2.5 mg/L), the drug still has a damaging effect on the cell surface at a much lower (clinically achievable) concentration (0.31 mg/L). Third, according to table I, the MICs of both amphotericin B and miconazole are 2.5 mg/L. However, in table 2 at this same concentration of drug, 0.08 and 10 mg of 5-fluorocytosine/mL are required to inhibit growth in the presence ofamphotericin B and miconazole, respectively.
Downloaded from http://jid.oxfordjournals.org/ at UQ Library on June 20, 2015
To the Editor-We appreciate the constructive comments by White et al. [I], who have extensive experience with cerebral malaria and other tropical infectious diseases. We agree that the diagnosis of cerebral malaria is only probable based on the evidence provided in our case [2]. We considered common causes of viral encephalitis, and these were excluded by negative serology. A possible coexisting infection due to one of the unusual arboviruses could not be excluded without more refined serologic tests. However, the dramatic clinical improvement after initiation of quinine and doxycycline therapy in a persistently febrile patient with sudden, rapidly deteriorating mental status supports the diagnosis of cerebral malaria. Furthermore, this therapeutic response and a rapid defervescence after antimalarial treatment are also inconsistent with the diagnoses of viral or postinfectious encephalitides.
lID 1992; 166 (November)
JIO 1992: 166 (November)
Correspondence
Reply To the Editor-Hopfer [I] raises several questions that deserve comment. We disagree that the results obtained were from poorly designed susceptibility tests and that our article will create inappropriate requests for clinical microbiology laboratories to do routine antifungal susceptibility testing. Specific concerns have been raised with regard to the methods used in our study [2] for the antifungal susceptibility testing. Although it was not reported in that article, a review of other experimental data (unpublished data) revealed that the strains tested had the same MICs on antibiotic medium no. 3 at neutral pH, and there are other data with other strains of Candida albicans tested against 5-fluorocytosine in Sabouraud dextrose broth that show a significant range of MICs of this drug. These data suggest that in our hands, there is a range ofMICs of 5-fluorocytosine that is not appreciably affected by the possible presence of any pyrimidine in the Sabouraud dextrose broth. Furthermore, the reduction in MICs that we saw with the addition of both drugs would argue against a falsely elevated MIC of 5-fluorocytosine. These observations suggest that our synergy studies appropriately reflect the interaction between amphotericin Band 5-fluorocytosine that we observed. With the use of appropriate controls, replicate assays, and standardized inoculum to avoid variability in our results, we have no reason to believe the assays were poorly designed. . Regarding the interpretation of table 2, it does not suggest that it required 0.08 and 10 mg/L 5-fluorocytosine to inhibit the growth of organisms in the presence of, respectively, amphotericin Band miconazole but that at higher concentrations of amphotericin B or miconazole, the cells are disrupted sufficiently to allow increased concentrations of 5-fluorocytosine to enter the cell, thus requiring less of the drug to inhibit growth ofthe organ-
Reprints or correspondence: Dr. J. Conly. Division of Infectious Diseases. Department of Medicine. Royal University Hospital. Saskatoon. Canada S7N OXO. The Journal of Infectious Diseases 1992;166:1197-8 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6605-0047$01.00
In conclusion, incidental findings based on poorly designed laboratory assays done on isolates from one patient hardly seem sufficient to imply recommendations for routine susceptibility testing of blood stream isolates of C. albicans. Roy L. Hopfer Department of Clinical Microbiology-Immunology, University ofNorth Carolina Hospitals, Chapel Hill References I. Conly J. Rennie R. Johnson J, Farah S, Hellman L. Disseminated candidiasis due to amphotericin B-resistant Candida albicans. J Infect Dis 1992; I 65:761-4. 2. Polak A, Scholer HJ. Fungistatic activity. uptake and incorporation of 5-fluorocysine in Candida albicans as influenced by pyrimidines and purines. I. Reversal to experiments. Pathol Microbiol 1973;39:
148-59.
ism. All MIC data were presented in SI units (Ie Systeme International d'Unites) [3]. Pertinent clinical observations were made in our article. The presence of persistently positive blood cultures for C. albicans despite an adequate dose and duration of treatment with amphotericin B and in a patient in whom no focal undrained collection can be found should arouse the suspicion ofresistance to amphotericin B. This clinical setting is not common, and we are certainly not recommending routine antifungal susceptibility testing in every patient who has candidernia, but susceptibility testing in the clinical setting we described would be quite justified and arguably good medical care and optimal use of laboratory services. Rather than "making a giant leap of faith," we merely presented an observation between an in vitro phenomenon with the reduction in the MIC of amphotericin B after the addition of 5-fluorocytosine with sterilization of blood cultures after addition of 5-fluorocytosine to the patient's therapeutic regimen. Although it was not stated in the paper, he had received a total of 400 mg of amphotericin B without having one negative blood culture and had not defervesced. Although it is possible that the addition of 5-fluorocytosine was coincidental to the cultures becoming negative, we think that this is very unlikely. After 5-fluorocytosine was added to the therapeutic regimen, there was defervescence, sterilization of blood cultures. improved clinical well being, and, even though the patient died, no evidence of viable C. albicans on extensive postmortem examination. We would be cautious to say that this does not imply cause and effect; stating that there is an association between the in vitro and in vivo observations is justified. There are now convincing data that have demonstrated a correlation between in vitro fungal susceptibility and the in vivo effect of antifungal agents [4, 5]. Furthermore, the combination of amphotericin Band 5-fluorocytosine has been shown to be more effective than either agent alone in vitro against many species of Candida [6].
J. Conly and R. Rennie Division of lnfectious Diseases, Department of Medicine. Royal University Hospital. Saskatoon. and Department of Microbiology. University ofAlberta Hospitals, Edmonton, Canada
Downloaded from http://jid.oxfordjournals.org/ at UQ Library on June 20, 2015
Fourth, unfortunately, there is no control in this single patient to determine outcome if 5-fluorocytosine were not given. The authors admit "there are no data to indicate there may be a better therapeutic outcome with the combination of 5-fluorocytosine and amphotericin B." They then make a giant leap of faith stating that their "results showed a significant reduction in the MIC of amphotericin B after addition of 5-fluorocytosine, which was associated with sterilization of blood cultures and a clinical benefit to the patient." In all likelihood, in a relatively intact immune setting, such "sterilization" would have happened with amphotericin B alone. One could argue that the addition of 5-fluorocytosine was coincidental to, not the cause of, cultures becoming negative. Even if their in vitro data are correct, 5-fluorocytosine did not cause a significant reduction in the MIC of amphotericin B, but rather the combination allowed use of lower concentrations of both drugs to attain the same in vitro effect.
1197
