Introduction Of Fluconazole Research Articles

Combination Therapy for HIV-Associated Cryptococcal Meningitis-A Success Story.

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far.

Does One Voriconazole Breakpoint Suit All Candida Species?

Non-species-dependent interpretative breakpoints for voriconazole and Candida species were proposed by the Antifungal Susceptibility Subcommittee of the Clinical and Laboratory Standards Institute in January 2005 (susceptible, ≤1 μg/ml; susceptible dose dependent [SDD], 1 to 2 μg/ml; and resistant, ≥4 μg/ml) (11). The proposed breakpoints were based on the MIC distribution profile, pharmacokinetic and pharmacodynamic parameters, and the relationship between in vitro activity and clinical outcome in six phase III studies. A clinical success of 65% (binomial range, 55 to 74%) was predicted with a breakpoint of ≤1 μg/ml. We are concerned that a 65% target for successful therapy is too modest, especially with the overall better results seen with the echinocandins and liposomal amphotericin B in large, recently completed studies (75 to 80% response rates) (7, 9, 12). Included in the phase III clinical studies were 1,630 cases of infection caused by the following species: Candida albicans, 54%; C. tropicalis, 15% (both MIC90s, 0.25 μg/ml); C. parapsilosis, 11% (MIC90, 0.06 μg/ml); C. krusei, 3% (MIC90, 1 μg/ml); and finally, C. glabrata, 17% (MIC90, 4 μg/ml). Thus, the vast majority of cases caused by isolates defined as susceptible were cases of C. albicans, C. tropicalis, and C. parapsilosis infection, with MICs 4 to 5 logs below the suggested breakpoint, and those not fully susceptible were isolates from C. glabrata and, to a minor extent, C. krusei infections. As the authors point out, the infecting species was also important in determining the outcome, along with the MIC. This raises the question about whether different breakpoints are needed for different species. C. glabrata, which was an uncommon pathogen before the introduction of fluconazole, lacks the capability to form pseudohyphae and has in some animal experiments been shown to be less virulent than C. albicans and C. tropicalis (1). In later clinical studies, C. glabrata has been associated with a higher mortality than other Candida species (4, 14); however, the possibility cannot be ruled out that a higher age and the fact that many patients initially receive fluconazole, which has inferior activity against C. glabrata, and not the greater virulence of the organism itself, could explain this higher mortality (2, 6, 10, 13). We therefore question if a non-species-dependent breakpoint for voriconazole susceptibility of ≤1 μg/ml is appropriate. We certainly feel that a resistance breakpoint of ≥4 μg/ml is too high, as clinical response rates are inadequate. Until further experience is achieved for such isolates, we recommend the use of microbiological cutoff values for C. albicans and other species for which the voriconazole MICs for wild-type isolates are very low. We are also not comfortable with the terminology “susceptible dose dependent” for voriconazole. This antifungal agent has nonlinear kinetics, and reporting SDD to clinicians invites dose escalation. An argument can be made for the therapeutic drug monitoring of voriconazole in any case, partly because low-dose drug exposure may predict clinical failure and partly because high-dose drug exposure may lead to additional toxicity, as clearly demonstrated with respect to liver function tests, and possibly for other clinical manifestations (3, 5, 8). Simple dose escalation on the basis of an MIC in the SDD range and a lack of clinical response could lead to toxicity, when a switch of therapies would be most appropriate.

Traitement antifongique des candidoses systémiques en réanimation

Hospital-acquired infections secondary to Candida have undergone a considerable recrudescence in the last decade. They still represent a substantial mortality rate, particularly in ICU patients. Their bad prognosis is mainly due to delay in treatment because of the difficulties involved in diagnosis. Clear indications for treatment resulting from an international consensus have not yet been established. The therapeutic regimen includes Amphotericin B, 5-fluorocytosin, azoles (fluconazole, itraconazole), and recently, new antifungals, mainly voriconazole and caspofungin. The use of amphotericin B is restricted because of its renal toxicity and the difficulty involved in its administration. Fluconazole use is still limited because of the possible development of fungal resistance especially in case of severe infection or of previous exposure to the drug. Indeed, the emergence of fluconazole resistance in Candida albicans as well as the frequency of other naturally resistant Candida species, such as Candida krusei, seems to have increased considerably since the introduction of fluconazole at the beginning of the 1990s'. However, since the appearance of new standardized and reasonably reliable methods to measure resistance, this worrisome rise in resistance seems to be the result of the absence of standard definition criteria rather than a microbiological cause. Furthermore, the interaction between the yeast and the host is so complex that the microbiological resistance has a low predictive value, if at all, for clinical resistance. Fluconazole should be the first choice for all patients without a documented or highly suspected resistance. Amphotericin B should be reserved for particular indications such us intracranial infections. The treatment should be adjusted according to the clinical evolution and the results of sensitivity tests.

The role of antifungal susceptibility testing in the therapy of candidiasis

Prior to the introduction of azoles, no real need for antifungal susceptibility testing (AFST) existed, as amphotericin B was the only agent available to treat systemic candidiasis. Introduction of fluconazole and itraconazole provided alternate, less toxic antifungal therapies. Intrinsic resistance of Candida krusei, decreased susceptibility of Candida glabrata, and development of resistance by Candida albicans (in mucosal disease in AIDS) to azoles led to development of our current AFST methodologies. The goal of AFST, like that of antibacterial susceptibility testing, is to predict clinical response, or at least to forecast failure. Although the ability of AFST to predict clinical outcome (clinical correlation) is still being fully elucidated, current methodologies do appear to reliably predict clinical resistance to azoles. Ready access to AFST is currently limited, affecting its timely use, but even with this lack of timeliness, AFST can still play an important role in patient care. Important potential roles include: 1) use in the development of local antibiograms to aid empiric selection of antifungals; 2) testing of isolates from candidemia or deep infection to aid in selection of long-term therapies; and, 3) the testing of isolates from recurrent mucosal disease to aid in selection of alternative regimens.

Stable susceptibility of Candida blood isolates to fluconazole despite increasing use during the past 10 years.

The prevalence of drug-resistant bacterial pathogens is very high in Taiwan. Accordingly, there was great concern that the introduction of fluconazole would result in rapid emergence of drug-resistant yeasts. Thus, we recommended in 1991 that fluconazole be used for treatment only. To explore the impact of this policy fluconazole susceptibility of Candida species blood culture isolates and outcome of patients with nosocomial candidaemia were monitored prospectively at National Taiwan University Hospital during 1994-2000. The MICs of fluconazole were determined by the disc diffusion method. There were 1095 episodes of nosocomial candidaemia during 1994-2000. Candida albicans was the most common species (50.4%), followed by Candida tropicalis (20.5%), Candida parapsilosis (14.2%) and Candida glabrata (12.0%). There were 0-2 isolates of Candida krusei per year. The incidence of nosocomial candidaemia and the proportion of C. glabrata peaked in 1996 and decreased thereafter. Fluconazole susceptibility was determined for 552 Candida blood isolates. Only 0.7% of blood isolates were resistant to fluconazole. Fluconazole susceptibility was 94.0% in 1994-1995 and 97.9% in 1999-2000 (P = 0.06). Attributable mortality for patients with nosocomial candidaemia was 43.2% in 1994-1995 and was 25% in 2000 (P = 0.005). Despite an increase in the incidence of nosocomial fungal infection and increased consumption of fluconazole from 1994 to 2000, there was no significant change in the susceptibility to fluconazole for bloodstream isolates of Candida species. These findings appear to be attributed to several factors. These include low prevalence of C. krusei and C. glabrata, changing patterns of use of antifungal drugs and broad-spectrum antibiotics, and efforts to improve the rational use of antifungal agents at our hospital.

Candidemia before and during the fluconazole era: prevalence, type of species and approach to treatment in a tertiary care community hospital.

The characteristics of candidemia before and after the introduction of fluconazole were compared at our institution. In the pre-fluconazole era (1986-89), the incidence of candidemia rose from 0.02% to 13% over the course of 4 y. Candida albicans accounted for 44/66 isolates (67%) and C. glabrata and C. parapsilosis were the predominant non-albicans species (9% each). In one-third of cases antifungal therapy was not given and the overall mortality rate was 55%. During the fluconazole era (1994-97), the incidence of candidemia remained constant between 1994 and 1996 at 0.09-0.11% and dropped to 0.06% in 1997. Bloodstream infection associated with neutropenia increased significantly but only accounted for 13% of cases; antifungal prophylaxis was not employed. The isolation of C. albicans decreased (n = 49; 50%) whereas isolation of both C. parapsilosis (n = 23; 24%) and C. tropicalis (n = 16; 16%) increased. The vast majority of patients received antifungal therapy and the overall mortality rate was 39%. These findings show that the incidence of candidemia rose steadily prior to the fluconazole era and then stabilized in spite of a shift towards non-albicans species. When candidemia was encountered in the fluconazole era, it was rare not to give antifungal treatment.

Resistance Pattern of 2 816 Isolates Isolated from 17 631 Blood Cultures and Etiology of Bacteremia and Fungemia in a Single Cancer Institution

The resistance pattern of 2 816 isolates from 17 631 blood cultures and the etiology of isolates causing bacteremia and fungemia among 14 591 admissions were investigated in an 80-bed single cancer institute during seven years (1990–1996) under the same empiric therapeutic antibiotic policy but with different prophylactic strategies. No change was found in the proportion of Gram-positive versus Gram-negative bacteria isolated from bacteremias (70% vs. 30%) during the past seven years. Furthermore, the proportion of coagulase-negative staphylococci and enterococci was about the same before and after the introduction of ofloxacin in prophylaxis. However, the proportion of Pseudomonas aeruginosa and Stenotrophomonas maltophilia causing bacteremia increased. There was no increase in Candida krusei and Candida glabrata after the introduction of fluconazole into our prophylactic regimen in 1992. Penicillin-resistance in viridans streptococci increased after penicillin was introduced into prophylaxis in acute leukemia in 1993. Until 1995 no quinolone-resistant Enterobacteriaceae were observed. Susceptibility to quinolones did not significantly change within the past seven years in Enterobacteriaceae after their introduction to prophylaxis in 1991, but Pseudomonas aeruginosa decreased from 90 to 58.2%. Glycopeptide resistance in enterococci and staphylococci was minimal in the observed period (0.9–4.3%).

Rapid speciation of the five most medically relevant candida species using PCR amplification and a microtiter plate-based detection system

Background: Diagnosis of disseminated candidiasis can be difficult, as patient symptoms are often vague and blood cultures negative despite systemic involvement. Rapid detection of Candida would be advantageous, as delays in initiating antifungal therapy increase mortality. Conventional blood culturing methods require at least 3-7 days for detecting and speciating isolates, especially non-albicans species. In contrast, DNA amplification techniques make it possible to detect Candida DNA directly from clinical samples, thus eliminating the need to culture. Methods and Results: This study describes a polymerase chain reaction (PCR)-based assay, which permits amplification and speciation of the five most medically relevant Candida species, which cause over 95% of all Candida infections, namely, C. albicans, C. tropicalis, C. (Torulopsis) glabrata, C. parapsilosis, and C. krusei. Speciating these isolates has become more important recently with the introduction of fluconazole, and antifungal drug that has lower nephrotoxicity than fungizone but a narrower host range. Conclusions: By using this PCR-based assay in conjunction with a rapid microtiter plate-based detection system, samples can be analyzed for Candida DNA from five species in a single day. This represents a significant time saving as compared with the more lengthy but commonly used techniques of agarose gel electrophoresis and Southern blot hybridization for PCR product detection. (Mol Diagn 1996 Jun;1(1):51-58)

Trends in the incidence and diversity of fungi recovered from urine

The diversity and incidence of fungal organisms recovered from the urine of patients at a tertiary level medical center was examined and compared over time. Mycologic culture records were examined for the 12 months prior to, and following the introduction of fluconazole to the hospital formulary in December 1991. 290 patients with 588 urine cultures from which fungi were recovered provided the database for this study.Candida albicans was the most common organism recovered in these cultures, followed byC. tropicalis, Torulopsis glabrata andC. parapsilosis. C. albicans was recovered alone in the urine of 54.4% of patients with funguria in the initial period and in 49.3% during the second. Funguria withT. glabrata nearly doubled (8.7% versus 17.1%) between these intervals (p<0.05). Fungal urine cultures in the second period were also noted more frequently to grow multiple organisms (mixed cultures), and to show a greater diversity of species. Review of the prescribing of antifungal agents to these patient groups revealed no clear pattern of prior drug exposure influencing this change. Although introduction of fluconazole at this institution was associated with a trend toward the recovery of a higher frequency of fungi in the urine which are notC. albicans, no direct evidence to implicate the introduction of this important new antifungal as the cause of this phenomenon was found.

Use of Antifungal Therapy in Hospitalized Patients I. Results Prior to the Marketing of Fluconazole

To evaluate the use of antifungal agents in hospitalized patients prior to marketing of fluconazole and to assess characteristics associated with their use. A cohort of hospitalized patients receiving topical or systemic antifungal therapy was monitored concurrently. Sixty-nine hospitals ranging in size from 100 to more than 500 beds, 70.1 percent affiliated with medical schools. Participating clinical pharmacists each identified 15 consecutive patients receiving systemic antifungal therapy and 5 consecutive patients receiving topical antifungal therapy at their institutions. Data collection began October 1989 and ended March 1990. All data collected were observational in nature, and no patient intervention was required. Characteristics of patients receiving antifungal therapy were compared using t-tests and chi-square tests. Utilization and patterns of use of antifungal therapy were reported. The most common risk factors necessitating antifungal therapy, in descending order, were: administration of broad-spectrum antibiotics and/or presence of invasive catheters, carcinoma, AIDS, leukemia or lymphoma, diabetes mellitus, solid organ or bone marrow transplantation, and chronic obstructive pulmonary disease. Five hundred seventeen patients received systemic therapy and 464 (89.7 percent) received a single systemic agent. Of these, 242 (52.2 percent) received amphotericin B, 215 (46.3 percent) received ketoconazole, 6 (1.3 percent) received flucytosine, and 1 (0.2 percent) received intravenous miconazole. Fifty-three patients received two systemic agents either concurrently or consecutively. Ketoconazole was most often used for presumed or documented oral, urogenital, or esophageal infections and amphotericin B was the preferred agent for disseminated infections and fungemia (p < 0.001). Almost half of the patients receiving amphotericin B or ketoconazole (48.3 percent) received these drugs as empiric therapy. Documented infections were more likely to be treated with amphotericin B (54.8 percent) than with ketoconazole (27.4 percent) (p < 0.001). The predominant fungal isolates were Candida albicans, Candida spp., and unspecified yeasts. Amphotericin B toxicity led to discontinuation of drug therapy in only 5.1 percent of cases. Two hundred sixty-nine patients (34.2 percent) received topical antifungal therapy only. Nystatin oral suspension was prescribed to 65.3 percent of the patients, clotrimazole troches to 23.0 percent, amphotericin B irrigation to 10.9 percent, and nystatin tablets to 0.8 percent. The utilization patterns of antifungal agents in this survey follow established therapeutic guidelines. Prior to the introduction of fluconazole, amphotericin B was the agent of choice for documented systemic fungal infections. Ketoconazole was more often used for prophylaxis of fungal infections and treatment of oral and esophageal infections.

Cryptococcal meningitis and AIDS.

Dr. William G. Powderly provides a comprehensive review of the state of our knowledge regarding cryptococcal infection in persons with infection due to human immunodeficiency virus type 1. The introduction of fluconazole and itraconazole increased insight into prognostic factors affecting these patients. The need to suppress this fungal infection in individuals with impaired immunity has greatly altered the management of cryptococcal meningitis; therapy for this condition was established by the landmark study conducted by the Mycosis Study Group in 1979 (Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in treatment of cryptococcal meningitis. N Engl J Med 1979;301:126-31). In this AIDS commentary Dr. Powderly clearly outlines the progress made through clinical investigations and the problems that remain to be resolved.

Changes in the spectrum of fungal isolates: results from clinical specimens gathered in 1987/88 compared with those in 1991/92 in the University Hospital Göttingen, Germany.

In the University Hospital in Göttingen, the spectra of fungal species in clinical specimens of respiratory secretions, bronchial secretions and urine were compared over periods of 15 months (10/87 to 12/88 and 1/91 to 3/92) before and after the introduction of fluconazole. The following changes could be demonstrated: 1. In all specimens analysed the number of Candida albicans isolates decreased, while the number of Candida tropicalis isolates remained almost unchanged. 2. During the observation period the number of Candida glabrata isolates doubled. In 1991 C. glabrata was second to C. albicans as the most common of all fungal isolates, appearing in 8.6% of all specimens. 3. The total number of Candida krusei isolates increased only slightly, but the rise in the number of isolates in bronchial secretions was statistically significant. 4. The prevalence of rarely isolated Candida yeasts, such as Candida guilliermondii, Candida lipolytica and Candida kefyr, and Candida isolates which were not further differentiated increased. 5. During the observation period the number of mixed cultures showed a fourfold increase. C. glabrata and C. krusei were associated in more than 75% of all isolates with C. albicans or C. tropicalis respectively. 6. The number of mould isolates increased. These changes in the spectra of fungal isolates are discussed with respect to the broad therapeutic and prophylactic usage of fluconazole in the University Hospital of Göttingen.

Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole.

In early 1990 fluconazole was introduced as a prophylactic antifungal agent after bone marrow transplantation. During the same year Candida krusei emerged as the chief candida pathogen among patients with bone marrow transplants. To determine whether there was a correlation between the introduction of fluconazole and the increased incidence of C. krusei, we conducted a retrospective study based on the medical, mycologic, and autopsy records of all adult inpatients who had undergone bone marrow transplantation (n = 296) or who had leukemia (n = 167) at the study center during 1989 and 1990. The 84 patients who received antifungal prophylaxis with fluconazole had a sevenfold greater frequency of C. krusei infection than the 335 patients who did not receive fluconazole (8.3 percent vs. 1.2 percent, P = 0.002), despite having a lower frequency of disseminated C. albicans and C. tropicalis infections (0 vs. 6.0 percent, P = 0.02). Ten of the 11 C. krusei infections were controlled by a combination of amphotericin B and flucytosine. Colonization by C. krusei was found in 40.5 percent of the patients who received fluconazole but in only 16.7 percent of those who did not receive it (P less than 0.0001). Colonization was independently associated with the prophylactic use of both fluconazole (odds ratio, 3.50; P less than 0.001) and norfloxacin (odds ratio, 2.53; P = 0.04). C. krusei was not susceptible to fluconazole in vitro. In patients at high risk for disseminated candida infections, suppression of bacterial flora and the more common candida pathogens may permit some less pathogenic, but natively resistant candida species, such as C. krusei, to emerge as systemic pathogens.

Cryptococcosis with AIDS: therapeutic strategies

Cryptococcosis is the most common life-threatening mycosis with AIDS. The combination therapy based on amphotericin B and flucytosine is furthermore the therapy of first choice, even after introduction of fluconazole. With a therapy maintained over a period of 6 weeks the combination is nearly always successful; a shorter treatment period leads to minor treatment success. Since no elimination of the pathogen is possible in cryptococcosis with AIDS a permanent relapse prevention is necessary. In this prevention strategy fluconazole is highly effective and at present the drug of first choice; it is as effective as amphotericin B. An additional advantage is the possibility of oral application.