Conference Summaries: ICAAC 2001, IDSA 2001, and ASTMH: Part II
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Editor’s Note: The following summaries represent a selection of papers from those presented at the meetings listed below. It is important to recognize that many of these summaries are extracted only from the published abstract, and it is possible that some of the material presented at the conferences may have differed. The abstracts can be found online at the URLs given. The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, Ill, Dec. 16-19, 2001; www.icaac.org. The 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco, Calif, Oct. 25-28, 2001; www.idsociety.org. The 50th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Atlanta, Ga, Nov. 11-15, 2001; www.astmh.org. — Stan Deresinski, MD, FACP
| Clinical Mycology (continued) |
Aspergillus: Clinical Disease and Diagnosis
Two personal cases and an additional 15 from the literature of aspergillosis involving the gastrointestinal tract as the primary site of infection were reviewed. Of the 7 patients for whom adequate information was available, none of whom had evidence of pulmonary infection, all had received induction chemotherapy for acute leukemia as well as broad-spectrum antibiotics. The infection presented as relapsed fever attributed to typhilitis and all 7 developed acute peritonitis requiring emergency surgery. Two of the 7 survived. (ICAAC #1637.)
Of 71 patients who received lung transplants, 1 died of disseminated aspergillosis prior to hospital discharge. Of the 44 patients who were discharged, 4 (9%) developed colonization but no infection with Aspergillus, while 15 (34%) developed infection with this fungus. These included 5 with tracheobronchitis, 9 with invasive infection, and 1 with widespread dissemination. All infections, except the last named, resolved after administration of antifungal therapy and reduction of immunosuppression. (ICAAC #1635.)
Aspergillus spp. were recovered from respiratory secretions of adults with cystic fibrosis with significantly greater frequency among those currently receiving, or who had ever received inhaled tobramycin when compared to those never receiving this therapy. (ICAAC #1249.)
The use of the BioRad Platelia AG ELISA assay for galactomannan in the diagnosis of invasive pulmonary aspergillosis was prospectively evaluated in a study of bronchial aspirates or bronchoalveolar lavage fluids from 210 immunocompromised patients, 25 of whom had the infection. The sensitivity and specificity of the assay were, respectively, 76% and 89%; the sensitivity of culture was only 44%. In 3 patients, the assay was positive on respiratory secretions before the assay on serum became positive. (ICAAC #846.)
In another larger study in which 153 patients were believed to have invasive aspergillosis, the sensitivity of the AG ELISA was 65% in those with definite, 16% in those with probable, and 25% in those with possible infection. The specificity, however, was 95%, but was lower in children (48%) than in adults (98%). (ICAAC #842.)
| Antifungals In Vitro & In Vivo |
Antifungal Susceptibility & Susceptibility Surveys. The geometric mean MIC of 53 clinical isolates of A flavus from 3 continents was 0.4 for amphotericin, 0.36 for itraconazole, 0.29 for voriconazole, 0.19 for posaconazole, and 0.64 mg/mL for ravuconazole. Study of a voriconazole-resistant clone (MIC = 12 mg/mL) obtained by in vitro passage found low-level resistance (2- to 4-fold increase in MIC) to itraconazole, posaconazole and amphotericin, but high-level (> 44 fold) cross-resistance with the voriconazole analog, ravuconazole. (ICAAC #271.)
Evaluation of 106 isolates of A fumigatus found that the MIC90 for amphotericin B was 1.0 mg/mL, while it was 0.5 mg/mL for both voriconazole and itraconazole and 0.03 mg/mL for posaconazole. An itraconazole-resistant reference strain retained susceptibility to voriconazole and posaconazole. (ICAAC #819.)
The SENTRY study reported susceptibility results for 213 isolates of filamentous fungi from 15 centers in the United States and Canada. Against the Aspergillus isolates ( n = 177, 105 of which were A fumigatus), the percent inhibited by < 1 mg/mL was 98% for posaconazole and ravuconazole, 92% for voriconazole, and 70% for itraconazole. (ICAAC #813.)
Antifungal Combinations. Using conidial suspensions and a radiometric method of susceptibility testing, it was found that combinations of either caspofungin or micafungin with amphotericin B were synergistic, while combinations of one of these echinocandins with voriconazole were additive and the combination of amphotericin with voriconazole was indifferent. (ICAAC #125.)
Itraconazole and terbinafine were synergistic or additive in vitro against Aspergillus spp., while fluconazole and terbinafine were synergistic against A fumigatus, A terreus, and A flavus, but indifferent against A niger isolates. Amphotericin and terbinafine were mostly indifferent or antagonistic as was the combination of flucytosine and terbinafine. Thus, this in vitro study suggests a possible benefit from the combination of terbinafine with azoles, but not with amphotericin or flucytosine, in the treatment of Aspergillus infections. (ICAAC #124.)
In a murine model of CNS infection with A fumigatus (100% mortality in controls by day 10), mice treated with amphotericin B had 40% survival at day 10, while those treated with itraconazole had 10% survival at day 10. Mice given combination treatment had 70% day-15 survival, a result that did not differ significantly from that observed with the individual therapies. (ICAAC #1614.)
In a study addressing the possibility of azole/polyene antagonism using a murine model of pulmonary aspergillosis, pretreatment with itraconazole was associated with a diminished mycological response and survival after treatment with amphotericin B. This apparent antagonism was not reversed by use of high doses of amphotericin. (ICAAC #1837.)
Postantifungal Effect. The duration of the postantifungal effect of amphotericin B on A fumigatus in vitro was 6 hours, while that of caspofungin was < 1 hour and those of itraconazole, voriconazole, posaconazole, and ravuconazole were < 30 minutes. Against C albicans, both caspofungin and amphotericin had prolonged postantifungal effects (8 hours and 6 hours, respectively), while those of the azoles were < 30 minutes. These results suggest that a prolonged postantifungal effect is associated with fungicidal activity. (ICAAC #105.)
The mean postantifungal effect of amphotericin B was 10 hours for A fumigatus, 4.3 hours for A terreus, 5.5 hours for A ustus, and 2.1 hours for A nidulans. No postantifungal effect was observed with itraconazole. (ICAAC #1839.)
Echinocandins. While the mean 24-hour geometric MICs of caspofungin against A niger, Emericella nidulans, and A terreus were all < 0.36 mg/mL, reduced activity was observed against the latter 2 species when the MIC was read at 48 hours. (ICAAC #113.)
Caspofungin improved survival without a reduction in residual fungal burden as determined by colony counting in neutropenic rabbits with invasive pulmonary aspergillosis. (ICAAC #1612.) However, using a real-time quantitative PCR (TaqMan) to quantitate Aspergillus DNA, both caspofungin and amphotericin B were highly effective in reducing fungal burden in a mouse model of invasive aspergillosis and the combination of the 2 drugs exhibited an additive effect in the majority of cases. (ICAAC #1835.) It is speculated that this discrepancy in results may be the consequence of an increase in colony counts as the result of disarticulation of hyphal segments in the presence of caspofungin, despite actual reduction in fungal burden.
Mutations in FKS1, the putative target of caspofungin activity, result in hypersensitivity of yeast to FK506, an immunosuppressive calcineurin antagonist. L-685,818, an analog of FK506 lacking immunosuppressive activity, was synergistic with caspofungin in vitro against clinical isolates of A fumigatus. (ICAAC #123.)
Polyenes. Liposomal amphotericin B, administered at the same dose, was therapeutically superior to Abelcet in a murine model of disseminated aspergillosis in which infection was achieved by intranasal challenge. This occurred despite the attainment of higher lung concentrations of Abelcet than of liposomal amphotericin, suggesting that the liposomal amphotericin B was more bioavailable in an active form. (ICAAC #1835.)
Azoles. Two hundred seventy-seven patients with confirmed invasive aspergillosis were randomized to receive, in an open fashion, either voriconazole or amphotericin B deoxycholate (1 mg/kg/d). Approximately one fourth had received allogeneic bone marrow transplants. Response rates at week 12 were greater in the voriconazole recipients (52.8% vs 31.6%; 95% confidence interval [CI] for the difference, 32.9-10.4%). Survival to week 12 was 70.8% in the voriconazole arm and 57.9% in those given amphotericin B (hazard ratio, 0.59; 95% CI, 0.40-0.88). As allowed by the protocol, amphotericin was continued for a median duration of only 11 days prior to change to other antifungal therapy, while voriconazole was continued for a median of 77 days. (ICAAC #680.)
Voriconazole inhibited conidiation and pigmentation in Aspergillus spp. at concentrations 8- to 16-fold lower than other azoles. Amphotericin, caspofungin, and micafungin did not inhibit these activities. (ICAAC #816.)
A voriconazole-resistant strain of A fumigatus retained virulence in a murine model of infection. (ICAAC #1613.)
Genetic analysis of 6 A fumigatus isolates resistant in vitro to voriconazole found results consistent with mutational alteration of the cytochrome P450-dependent 14a-sterol demethylase as the cause of resistance. (ICAAC #817.)
Immunomodulatory Therapy. Macrophages obtained by bronchoalveolar lavage from dexamethasone-treated mice have reduced capacity to secrete IL-1a, TNFa, and MIP-1a in response to conidia of A fumigatus ex vivo. This effect was prevented by simultaneous administration of GM-CSF to the animals. (ICAAC #129.)
| Miscellaneous Filamentous Fungi |
Alternaria. A case of Alternaria infection of the maxilla, oral cavity, and nasal bridge, present for 22 years and recalcitrant to multiple therapies clinically resolved during treatment with voriconazole. (IDSA #609.)
Fusarium. Of 75 patients at a cancer hospital from whom Fusarium spp. had been recovered, 35 had definite infection with skin lesions caused by this fungus. Twenty-one of the 35 had disseminated infection, while infection was judged to be localized in 14. (IDSA #637.)
Ravuconazole, itraconazole, and voriconazole each had activity against F verticelloides, but none were active against F solani. (ICAAC #810.) Voriconazole was effective in a murine model of intravenous infection with F solani. (ICAAC #1604.)
Liposomal amphotericin B, at a dose of 20 mg/kg/d improved survival in a murine model of disseminated infection with Fusarium verticelloides. Treatment at a dose of 1.5 mg/kg/d gave results not different from those observed in the infected control (untreated) animals. (ICAAC #1830.)
Pseudallescheria boydii & Scedosporium apiospermum. Ravuconazole, itraconazole, and voriconazole each had modest activity against S apiospermum. (ICAAC #810.) Both fluconazole and posaconazole treatments improved survival in a murine model of infection with P boydii. (ICAAC #1615.)
Scedopsorium prolificans. S prolificans isolates from 3 patients, as well as from ambient air, were indistinguishable by DNA fingerprinting using the PCR-based RAPD analysis. Their MICs against voriconazole were 2.0-4.0 mg/mL. (ICAAC #269.) S prolificans was resistant to ravuconazole, itraconazole, and voriconazole. (ICAAC #810.)
Amphotericin B and pentamidine were synergistic in vitro against all 28 isolates of Scedosporium prolificans tested. (ICAAC #121.)
Zygomycetes. Posaconazole and amphotericin B each reduced fungal burden and improved survival in a murine model of Mucor spp. infection; itraconazole was ineffective. (ICAAC #1616.)
Ravuconazole and itraconazole, but not voriconazole, had in vitro activity against zygomycetes other than Mucor spp. against which none of the 3 were active. (ICAAC #810.)
| Endemic Mycoses |
Histoplasmosis capsulatum. Investigation of the histoplasmosis outbreak among US spring-breakers in Acapulco in March 2001 found 229 students from 44 colleges in 23 states who met the clinical case definition. The laboratory case definition (M or H immunodiffusion band, CF titer > 1:32, or positive culture of histopathology) was met by 65 of 171 (38%) with only a single serum specimen and 20 of 23 (87%) with paired sera. Investigation found that infection was associated with staying in 1 identified hotel. (IDSA #30.)
A retrospective case-control study of AIDS patients with either histoplasmosis or PCP found that a serum LDH level > 600 IU was suggestive of histoplasmosis (mean LDH, 1068 IU/L) rather than PCP (mean LDH, 375 IU/L). A level > 450 IU/L had a sensitivity of 70% and a specificity of 80% in the diagnosis of histoplasmosis. (IDSA #773.) In a separate study, an LDH at day 3 of > 2000 IU/L was one of the factors associated with increased mortality in disseminated histoplasmosis in AIDS patients. (IDSA #774.)
Differential display RT-PCR was used to compare mRNA from an isogenic matched set of clinical isolates of H capsulatum that became resistant to fluconazole during therapy. Of 11 cDNA fragments representing mRNA that had been overexpressed in the resistant isolates, 1 was a homolog of the PSE 1 gene of S cerevisiae that is necessary for the nuclear localization of the multidrug resistance transcription factor PDR1. (ICAAC #823.)
Coccidioides immitis. The incidence of coccidioidomycosis in renal and heart transplant programs within the endemic area is reported to be 4-8%, with most infections occurring in the first year after transplantation. At the Phoenix Mayo Clinic, candidates for orthoptic liver transplantation with either a history of coccidioidomycosis or a positive serological test receive prophylactic fluconazole, while those with neither criteria are followed with serological tests every 3 months. Only 3 of 57 patients met criteria and were given fluconazole prophylaxis—none had subsequent disease reactivation. One of 54 who did not receive prophylaxis developed active coccidioidomycosis, which was successfully treated. (ICAAC #828.)
Increased CD69 expression on the surface of CD3+ lymphocytes in response to a coccidioidal antigen in vitro correlated with seropositivity. (IDSA #618.)
Two of 3 recipients of organs (kidney, liver) from a donor subsequently found to have coccidioidal meningitis developed rapidly fatal disseminated coccidioidomycosis. (IDSA #619.)
| The Immunocompromised Host & Fungal Infection |
Neutropenia. A meta-analysis of 7 studies involving 2181 patients or episodes found that the relative risk for the development of proven invasive fungal infection was 0.55 (P = 0.01) for neutropenic patients randomized to itraconazole prophylaxis compared to those given placebo. The relative risk of death from invasive fungal infection was reduced (0.17, P = 0.01) in those receiving itraconazole oral solution, but not in those receiving the capsule form of the drug. Overall mortality was not affected. (ICAAC #681.)
Most cases of breakthrough candidemia, defined as occurring in the face of at least 7 days of antifungal administration, at one cancer hospital were due to either C kruseii or C glabrata. (IDSA #622.)
Surgery. A retrospective cohort study found a trend for decreased progression to invasive candidiasis, but no difference in mortality, among surgical ICU patients who had received systemic antifungals. (ICAAC #1463.)
Prematurity. A prospective study throughout Germany identified 137 preterm or term infants with systemic fungal infections. Four were due to Aspergillus spp., 101 to C albicans, and the remaining 25 were due to nonalbicans Candida (16 due to C parapsilosis). (ICAAC #833.)
Solid Organ Transplants. The incidence of invasive candidiasis declined significantly in the last decade among liver transplant recipients at the University of Pittsburgh. (ICAAC #836.)
A case-control study of renal transplant recipients found that the combined use of the immunosuppressants sirolimus and mycophenolate was a significant risk factor for the development of invasive aspergillosis. (IDSA #616.)
| Antifungals |
Polyenes
Liposomal amphotericin B. Acute infusion-related reactions during infusion of liposomal amphotericin B (L-AMB) can be categorized as complexes of: 1) chest pain, dyspnea, and hypoxia; 2) severe abdominal flank or leg pain; or 3) flushing and urticaria. Examination of the records of 84 patients who received L-AMB in clinical trials found such reactions in 29 (35%), with the incidence increasing dramatically from 1994-1995 (12% and 17%, respectively) to 1996 -1999 (> 40%). Eighty-six percent of reactions occurred during the first 5 minutes of infusion; all resolved rapidly after IV administration of diphenhydramine. Of those experiencing the reaction, 93% were rechallenged and were able to tolerate continued L-AMB administration. Examination of 422 additional patients from 64 centers found an overall frequency of acute infusional reactions of 20%—however, 29 (45%) of the centers reported no such reactions. (ICAAC #835.)
Echinocandins
Caspofungin. Caspofungin exposure was increased by approximately 50% in patients with mild hepatic insufficiency (Child-Pugh score, 5-6) and approximately 75% in those with moderate hepatic disease (Child-Pugh, 7-9). While no reduction in caspofungin dose is recommended in patients with mild hepatic insufficiency, the dose in those with moderate disease should be reduced to 35 mg daily after the 70 mg/d day-1 loading dose. (ICAAC #14.)
Coadministration of caspofungin and tacrolimus to healthy volunteers was associated with an approximately 20% reduction in tacrolimus exposure; no effect on caspofungin pharmacokinetics was observed. (ICAAC #12.)
The Etest correlated reasonably well with standard methods of susceptibility testing of caspofungin against Aspergillus and Candida spp. (ICAAC #580, ICAAC #582.)
Azoles
Fluconazole. The clearance of fluconazole in anuric patients undergoing continuous venous-venous hemodialysis was equivalent to that of individuals with normal renal function and, therefore, dosing should be the same. (ICAAC #31.)
Itraconazole. Two patients simultaneously receiving liposomal amphotericin B and the intravenous formulation of itraconazole developed hepatotoxicity after 112 days and 75 days of therapy, respectively. Hepatic enzymes normalized 17 and 34 days after discontinuation of itraconazole. (IDSA #650.)
A nanocrystal formulation of itraconazole was given intravenously for 14 days to patients receiving cyclosporin. The drug was well tolerated, although 2 patients had transient hypotension. The terminal serum half-life was 346 ± 225 hours and serum levels of at least 500 ng/mL were maintained in some patients for at least 9 days after completion of treatment. Cyclosporin dosage reduction of approximately one third was required in most patients. (ICAAC #32.)
Voriconazole. Voriconazole is solubilized for IV administration by use of the excipient, sulphbutylether-b-cylcodextrin (SBECD). In fact, patients receiving a typical loading dose of voriconazole of 6 mg/kg also receive 96 mg/kg of the excipient. A 10-day study in 9 healthy volunteers found that clearance of SBECD was similar to creatinine clearance and there was no evidence of accumulation. (ICAAC #23.)
The clearance of voriconazole after oral administration, as well as exposure to the drug’s N-oxide metabolite, were reduced by approximately one half in the presence of hepatic cirrhosis. It is suggested that cirrhotics receive the usual loading dose, but half the usual maintenance dose of voriconazole. (ICAAC #16.)
Coadministration of voriconazole with omeprazole in healthy volunteers was associated with significant increases in AUC24 and Cmax of the latter, findings consistent with inhibition of CYP2C19 and CYP3A4 by voriconazole. (ICAAC #19.) In in vitro studies, voriconazole inhibited tacrolimus metabolism by its effects on CYP3A4. In one liver transplant patient, the addition of voriconazole to tacrolimus therapy led to a marked increase in trough concentrations of the latter, indicating the need for close monitoring of tacrolimus levels when the combination is used. (ICAAC #21.) In a study involving 14 healthy volunteers, coadministration of tacrolimus and voriconazole resulted in a mean 3.2-fold increase in tacrolimus AUC and 2.2-fold increase in its Cmax. (ICAAC #20.) In single-dose studies, voriconazole administration did not affect the pharmacokinetics of mycophenylate fofetil. (ICAAC #24.)
Visual disturbance, most often altered visual perception and blurred vision, has been frequently reported by voriconazole recipients, although the resultant frequency of drug discontinuation is < 1%. These adverse events usually occur approximately 30 minutes after a dose and last for approximately 30 minutes, occurring most often in the first week of therapy and often subsequently diminishing or disappearing despite continuation of the drug. No structural correlates or long-term sequelae have been detected. Extensive testing found evidence of a reversible decrease in amplitude of the electroretinogram, implicating the retina as the site of dysfunction. A reversible alteration in color discrimination was also observed. (ICAAC #639.)
The risk of elevation of serum-hepatic enzymes in patients receiving voriconazole in clinical trials was concentration dependent. (ICAAC #18.)
| Cryptococcus neoformans |
The French Cryptococcosis Study Group reported 28 cases of primary cutaneous cryptococcal infection. Half the patients were immunocompromised and 15 lived in rural areas. There was a history of skin injury in 27 patients, frequently caused by "wood sticks" (9 patients) and often contaminated with bird droppings (14 patients). The median interval from injury to diagnosis was 30 days. Only a single skin lesion was seen in 24 patients (86%); these included 13 with whitlow. All patients from whom samples were obtained had negative blood (10) and CSF (12) cultures. (ICAAC #827.)
In a randomized, placebo-controlled trial involving 79 HIV-infected patients with cryptococcal meningitis treated with amphotericin B plus flucytosine for 14 days followed by fluconazole, the coadministration of interferon gamma was associated with a trend (not statistically significant) toward more rapid sterilization of CSF and fall in CSF cryptococcal antigen titer. (ICAAC #LB-10.)
AIDS patients with cryptococcal meningitis and an opening CSF pressure > 20 cm H2 were randomized to receive, in addition to antifungal therapy, either dexamethasone (9 patients) or repeated lumbar puncture (12 patients) to control intracranial hypertension. There was no difference in microbiological or clinical outcomes, or in control of CSF pressure, although CSF was sterilized more quickly in the repeat LP group (50% sterile vs 22% at 15 days; P < 0.05). (IDSA #760.)
C neoformans isolates were obtained during repeated relapses of cryptococcal meningitis in a patient maintained on fluconazole in doses as high as 1600 mg daily. No ergosterol could be detected in cell membranes of isolates from the 4th and 5th episodes. The isolates remained azole susceptible, but were tolerant to amphotericin B. (ICAAC #110.)
Paradoxical reactions associated with immune reconstitution were seen in 4 AIDS patients with cryptococcosis 2-11 months after initiation of HAART. These reactions included meningeal irritation with increased intracranial pressure, lymphadenopathy, and a cavitating pneumonia; cultures were negative in each case. (IDSA #761.)
An additional 5 AIDS patients with cryptococcosis with immune reconstitution-related paradoxical reactions were described. Two developed meningeal irritation, 2 developed new pulmonary nodules, and 3 developed enlarged lymph nodes 2-31 months after the initiation of HAART. Plasma cryptococcal antigen titer remained stable and cultures remained negative; all improved with or without anti-inflammatory drug therapy. (ICAAC #674.)
Azoles and human serum (but not CSF) exhibit synergistic fungicidal activity against C neoformans var. neoformans. In contrast, both human serum and CSF interfere with the fungicidal activity of azoles against C neoformans var. gatti. (ICAAC #809.)
| Rhodotorula |
A patient with chronic vaginitis due to an azole-resistant Rhodotorula rubrae strain recalcitrant to multiple therapies was successfully treated with a prolonged course of vaginal douching with amphotericin B (50 mg/L) as well as orally administered amphotericin. (IDSA #163.)
The WBC of peritoneal fluid in a case of CAPD-associated peritonitis due to R rubra was only 35/mm3; routine culture was negative, but the organism was recovered from fungal culture. In this case, as well as 5 gleaned from the literature, all required removal of the peritoneal catheter and treatment with either IV or IP amphotericin B. (IDSA #164.)
| Pneumocystis carinii |
A meta-analysis of 6 studies found that the sensitivity of immunofluorescent techniques for visualization of Pneumocystis carinii in respiratory secretions was significantly greater than that observed with histochemical techniques. (ICAAC #844.)
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