Conference Summaries of ICAAC 2001, IDSA 2001, and ASTMH 2001: Part I
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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, Illinois, Dec. 16-19, 2001; http://www.icaac.org. The 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco, California, 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; http://www.astmh.org.— Stan Deresinski, MD, FACP
| Clinical Mycology |
Candida: Clinical Disease and Diagnosis
Bloodstream Infections. A large population-based surveillance study found that the average annual adjusted incidence of candidemia was 10.3 per 100,000 population and the overall crude mortality was 38%. (IDSA #641.) Based upon examination of approximately 20% of all community hospital discharges in the United States, it is estimated that the total number of hospitalizations in which disseminated candidiasis played a role in 1997 was 10,595, an increase from 8100 in 1993. The estimated in-hospital mortality was 26.9%. (IDSA #833.)
Growth as a biofilm plays a key role in vascular catheter-related infections. Candida albicans is a more potent producer of biofilm in vitro than the (usually) nonpathogenic Saccharomyces cerevisiae. The MICs of amphotericin and fluconazole increased from, respectively, 0.5 mg/mL and 1.8 mg/mL when the organism was grown planktonically, to 8 mg/mL and 128 mg/mL with late growth as biofilm. (ICAAC #117.)
Mature biofilms formed by 7 strains of C albicans exhibited high-level resistance to fluconazole (MIC50 > 1024 mg/mL) regardless of their degree of susceptibility as free-living (planktonic) cells. (ICAAC #120.) Using simulated antifungal regimens in vitro and single lumen central venous catheters colonized with a biofilm of Candida, it was found that neither amphotericin B nor azole therapy completely eradicated the organisms. The overall rank of antifungal activity was: amphotericin (1 mg/kg/d) > amphotericin 0.5 mg/kg/d) > voriconazole (200 mg q 12 h) > fluconazole (800 mg q.d.) > fluconazole (400 mg q.d.). (ICAAC #108.)
It has been suggested that the decreased susceptibility to antifungal agents observed when organisms grow as biofilms rather than in suspension may be due to increased drug efflux. However, biofilms formed by C albicans mutants deficient in drug efflux pumps displayed intrinsic resistance to fluconazole equivalent to that seen in parent strains, indicating that upregulation of efflux pumps does not account for reduced susceptibility to fluconazole in biofilms. (ICAAC #119.)
A review of 77 episodes of candidemia in 73 immunocompromised pediatric patients found that 53% were due to C albicans, 18% to C parapsilosis, and 16% to C tropicalis. Candidemia contributed to death in 17% of the patients. Central venous catheter removal did not influence survival. (IDSA #162.)
In a series of 63 AIDS patients with candidemia, 88% had classic risk factors (IV lines, etc), although only 1 patient had neutropenia. The mortality was 22.2%. (IDSA #766.)
In a review of current guidelines for management of intravenous catheter-related infections, the recommendations for those with Candida spp. infection were: remove the catheter and administer systemic antifungal therapy to all patients with amphotericin B recommended for suspected catheter-related candidemia if the patient is hemodynamically unstable or has received prolonged fluconazole administration. Fluconazole therapy is acceptable if the patient is hemodynamically unstable and has not recently received fluconazole therapy, or if the isolate is known to be fluconazole susceptible. Treatment should continue for 14 days after the last positive blood culture and resolution of symptoms of infection has been achieved. Amphotericin B should be used for C kruseii infection. If there is documented catheter-related fungemia, tunneled or implanted catheters should be removed. In the presence of septic thrombosis, the catheter should be removed and surgical excision is recommended; anticoagulation should be used for great central venous septic thrombosis. (ICAAC #428.)
More than 200 patients with candidemia (C krusei excluded) received fluconazole (800 mg q.d. for 14 days after resolution of symptoms) with, by randomization, either amphotericin B deoxycholate (0.7 mg/kg/d for the first 3-8 days) or placebo. Placebo recipients had higher Apache II scores at baseline. Success (bloodstream clearance plus symptom resolution) was observed in 56% of those randomized to fluconazole plus placebo and 68% in those given fluconazole plus amphotericin B (P = 0.045). By Kaplan-Meier analysis, the success rates at 30 days were, respectively, 57% and 67% (P = 0.1); there was failure to clear candidemia in 17% of fluconazole/placebo and 7% of fluconazole/amphotericin recipients (P = 0.02). While antagonism was not demonstrated, the results were confounded by the quirk in randomization that places sicker patients in the fluconazole plus placebo group. (ICAAC #681a.)
Oropharyngeal Infection. In a prospective study of prophylaxis of oropharyngeal candidiasis in HIV-infected patients, C albicans isolates from 12 of 42 fluconazole recipients became resistant to this triazole. Of the remaining 30 patients, 8 (27%) experienced replacement of C albicans with C dubliniensis, a result not seen in any of those whose C albicans had become fluconazole resistant. (ICAAC #1620.)
Ninety-three patients with oropharyngeal candidiasis were randomized to receive fluconazole either as an oral suspension or as capsules with resultant clinical success rates of 93% in each arm at the end of therapy, although there was a trend toward faster resolution of symptoms in the suspension recipients. Mycological response at the end of therapy did not differ between the groups (67% and 71% at end of therapy). (ICAAC #1624.)
In a study of the possible role of bacterial and fungal oral flora on the severity of oral mucositis in autologous stem cell recipients, a decrease (median 99%) in colonization with both was seen in 11 of 12 patients until day 6, while mucositis and pain increased. The percentage with positive fungal cultures increased to 86% by day 100. It was concluded that oral mucositis in these patients was the result of chemotherapy, rather than the result of microbial overgrowth. (ICAAC #1251.)
Esophagitis. Caspofungin and fluconazole treatment (both given IV) of esophageal candidiasis had similar efficacy and rates of adverse events. (ICAAC #675.) Furthermore, caspofungin was effective in the treatment of 18 of 25 (72%) cases of esophagitis caused by Candida spp. with reduced susceptibility to fluconazole. (IDSA #646.)
Peritonitis. Candida was recovered from intra-abdominal fluid of 23 of 62 (37%) Taiwanese patients with perforated peptic ulcer. Only 8 of the 23 were given antifungal therapy. Five (22%) patients with Candida peritonitis died, while only 1 of 39 (2.6%) without recovery of this fungus from peritoneal fluid did so (P = 0.023). (ICAAC #1630.) An apparent increased mortality in Candida-infected patients was also observed in a case-control study that found that isolation of Candida spp. from the peritoneal cavity of patients undergoing abdominal surgery was an independent risk factor for death. (IDSA #222.)
Vulvovaginitis. Five hundred ninety-three yeast isolates were obtained from 428 patients with vulvovaginitis. Four hundred twelve (69%) were C albicans, 112 (19%) were C glabrata, 29 (5%) C parapsilosis, 12 (2%) C krusei, 9 (1.5%) S cerevisiae, 8 (1.3%) C tropicalis, and 1 each of C lusitaniae and Trichosporon spp. Among the Candida, 100% of C krusei and 15.2% of C glabrata were resistant to fluconazole, but all others remained susceptible or susceptible-dose dependent. Resistance to itraconazole was seen in 15.2% of C glabrata, 2.4% of C parapsilosis, 58.3% of C krusei, as well as 55.6% of S cerevisiae. A 4-fold or greater rise in MIC in serial isolates was observed in only 1 of 80 patients with recurrent vaginitis. (ICAAC #112.)
Ten women, all of whom had previously received multiple antifungal agents, with chronic recurrently symptomatic vulvovaginitis due to C krusei were seen at 1 center over 15 years. Recommended treatment involves clotrimazole vaginal suppositories (clotrimazole MIC90 = 0.25 mg/mL) or boric acid vaginal capsules. (ICAAC #885.)
In a trial of prophylaxis of vaginal candidiasis, 173 HIV-infected women were randomized to receive weekly fluconazole or placebo. Twenty-one assigned fluconazole and 25 assigned placebo used open-label fluconazole for recurrent episodes of candidiasis. Examination of serial Candida isolates found no difference between fluconazole and placebo recipients in the incidence of fluconazole resistance. (ICAAC #1631.)
Central Nervous System Infections. A retrospective review of 8 children and 7 adults with Candida meningitis at 1 institution found that 10 infections were due to C albicans, 3 to C parapsilosis, 2 to C tropicalis, and 1 each to C glabrata and C famata. All cases were of nosocomial origin and all patients had predisposing conditions, including hydrocephalus, recent neurosurgical procedures, and CSF shinting. Fifty-three percent survived, while 27% died as the result of the infection. (ICAAC #1626.)
Diagnosis. The Platelia Candida Ag and Ac tests are designed to detect, respectively, mannan and antibody to mannan. In 12 proven cases of invasive candidiasis, 1 or both test(s) was/were positive in 91%, with specificity of 77%, positive predictive value of 77%, and negative predictive value of 91%. Falsely positive tests were seen in some patients with severe mucositis and Candida colonization. In some patients with hepatosplenic candidiasis, the test(s) became positive prior to the presence of radiologic findings. (ICAAC #847.)
The Glucatell test, a chromogenic Limulus amebocyte lisate-based assay system that detects fungal b-D-glucan, in a study of serum from 30 patients with candidemia and 30 healthy controls, had a sensitivity of 96.6% and specificity of 93.3%. (ICAAC #841.)
| Antifungals In Vitro & In Vivo |
Antifungal Susceptibility Surveys. One hundred fifteen responding microbiology lab directors based in US teaching hospitals reported a median number of 9 Candida isolates per 1000 inpatient days (range, 1-145). Three fourths reported doing antifungal susceptibility testing, but only 22 hospitals performed the test on-site and only two thirds of these used the standard NCCLS M27-A method. Only 1% of all isolates were susceptibility tested. The mean time to obtain MIC results was < 7 days for 86% of on-site testers, but only 35% for off-site testers. (ICAAC #567.)
The SENTRY surveillance study of hospitals in the Americas and Europe studied more than 2000 bloodstream Candida spp. isolated over 3 years ending Dec. 31, 2000. The prevalence of antifungal resistance increased with increasing patient age. The MIC90 of amphotericin B against C albicans was 1 mg/mL, while it was 4.0 mg/mL against C glabrata and 8.0 mg/mL against C krusei. While there is no agreed upon susceptibility breakpoint for amphotericin, most would consider the latter 2 values to be in the resistant category. (ICAAC #115.)
The fluconazole MIC90 against 733 C albicans isolates at 39 US medical centers was 2.0 mg/mL, while that of C glabrata (n = 45) was 32 mg/mL and C krusei (n = 50) > 64 mg/mL. These results did not change between 1996 and 1998. (IDSA #642, #643.)
Echinocandins. The MIC90 of caspofungin against a large number of Candida spp. isolates "considered refractory to antifungal therapy" was < 0.125 mg/mL. (ICAAC #113.)
The postantifungal effect of the echinocandin, micafungin (FK-463), against Candida spp. was concentration dependent. At concentrations equal to the MIC it ranged from -0.3 hours to 11 hours. At 4 ´ MIC, the effect ranged from 0.9 hours to > 19.5 hours. (ICAAC #2204.) Both caspofungin and amphotericin B were therapeutically effective, while fluconazole was ineffective, in p47phox knockout mice infected with C glabrata. (IDSA #640.)
Azoles. Candida is generally tolerant to azoles—ie, the concentration required for fungicidal activity is greatly in excess of that required for fungistasis usually clinically unattainable. Disruption of the single gene encoding calcineurin in C albicans changed the activity of both fluconazole and terbinafine against this organism from fungistatic to fungicidal. Thus, consistent with other data demonstrating that cyclosporin renders fluconazole fungidical against C albicans, calcineurin is necessary for tolerance to these agents. (ICAAC #1090, ICAAC #1845.) Studies in S cerevisiae and C Albicans also demonstrated a role for the PKC (cell integrity) MAP kinase pathway in tolerance to inhibitors of sterol biosynthesis. (ICAAC #1844.)
Nonetheless, azoles can be rapidly fungicidal against Candida spp. at concentrations > 100 ´ MIC, an effect previously proposed to be the result of direct toxicity to the fungal cell membrane. However, studies reported here suggest that this effect, which is MIC-dependent, is the result of inhibition of the ERG 11 product, lansoterol demethylase. (ICAAC #103.)
A study of 40 isolates of C glabrata resistant to azole antifungal agents from a single hospital found overexpression of drug efflux pumps and/or ERG 11 mutations in the majority. (ICAAC #824.)
A review of pharmacodynamics in antifungal therapy indicated that the 24 hour AUC/MIC ratios are the critical PK/PD parameter for the triazoles and that animal models indicating that a free-drug AUC24/MIC ratio of > 25-50 is associated with treatment efficacy. Examination of human clinical trials with fluconazole also suggest that AUC24/MIC > 25 is associated with microbiological and clinical success. (ICAAC #1777.)
Polyenes. Liposomal nystatin had efficacy similar to amphotericin B in reduction of the fungal burden in organs other than the brain in a rabbit model of invasive candidiasis. The lesser activity against CNS Candida was associated with brain tissue concentrations below the MIC of the infecting isolate. (ICAAC #1606.)
| Immunomodulatory Therapy |
Mycograb, a human recombinant antibody targeting heat shock protein 90 of C albicans, was administered to 4 patients with invasive candidiases who were receiving Abelcet with good tolerance and possible clinical improvement. (ICAAC #1632.)
Moxifloxacin protected cyclophosphamide-treated mice from experimental C albicans lung infection, with reduction in mortality, despite a lack of direct antifungal activity. This was associated with increased interferon gamma in lung tissue, a finding consistent with previous data indicating moxifloxacin-associated enhanced cytokine production in mice given cyclophosphamide. (ICAAC #1608.)
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