Russell E. Lewis

Zygomycosis in a Tertiary-Care Cancer Center in the Era of Aspergillus-Active Antifungal Therapy: A Case-Control Observational Study of 27 Recent Cases

BACKGROUND Anecdotal evidence suggests a rise in zygomycosis in association with voriconazole (VRC) use in immunosuppressed patients. METHODS We performed prospective surveillance of patients with zygomycosis (group A; n = 27) and compared them with contemporaneous patients with invasive aspergillosis (group B; n = 54) and with matched contemporaneous high-risk patients without fungal infection (group C; n = 54). We also performed molecular typing and in vitro susceptibility testing of Zygomycetes isolates. RESULTS Nearly all patients with zygomycosis either had leukemia (n = 14) or were allogeneic bone marrow transplant recipients (n = 13). The Zygomycetes isolates (74% of which were of the genus Rhizopus) had different molecular fingerprinting profiles, and all were VRC resistant. In multivariate analysis of groups A and C, VRC prophylaxis (odds ratio [OR], 10.37 [95% confidence interval [CI]], 2.76-38.97]; P = .001), diabetes (OR, 8.39 [95% CI, 2.04-34.35]; P = .003), and malnutrition (OR, 3.70 [95% CI, 1.03-13.27]; P = .045) were found to be independent risk factors for zygomycosis. Between patients with zygomycosis (after excluding 6 patients with mixed mold infections) and patients with aspergillosis, VRC prophylaxis (OR, 20.30 [95% CI, 3.85-108.15]; P = .0001) and sinusitis (OR, 76.72 [95% CI, 6.48-908.15]; P = .001) were the only factors that favored the diagnosis of zygomycosis. CONCLUSIONS Zygomycosis should be considered in immunosuppressed patients who develop sinusitis while receiving VRC prophylaxis, especially those with diabetes and malnutrition.

Antifungal drug resistance of pathogenic fungi

Pathogenic fungi have many complex mechanisms of resistance to antifungal drugs. Information about the clinical, cellular, and molecular factors contributing to antifungal-drug resistance continues to accumulate. We critically review the diagnosis, epidemiology, and mechanisms of antifungal drug resistance of pathogenic fungi. Better understanding of this resistance should assist in developing better detection strategies for preventing and treating refractory mycoses in the future.

Delaying Amphotericin B–Based Frontline Therapy Significantly Increases Mortality among Patients with Hematologic Malignancy Who Have Zygomycosis

BACKGROUND Zygomycosis is an emerging opportunistic mycosis among immunocompromised patients with a particularly poor prognosis. METHODS We analyzed the impact of delaying effective amphotericin B-based therapy on outcome among 70 consecutive patients with hematologic malignancy who had zygomycosis in our institution during the period 1989-2006. We used classification and regression tree analysis to identify the mortality breakpoint between early and delayed treatment. RESULTS Delayed amphotericin B-based therapy (i.e., initiating treatment >/=6 days after diagnosis) resulted in a 2-fold increase in mortality rate at 12 weeks after diagnosis, compared with early treatment (82.9% vs. 48.6%); this remained constant across the years of the study and was an independent predictor of poor outcome (odds ratio, 8.1; 95% confidence interval, 1.7-38.2; P = .008) in multivariate analysis. Active malignancy (P = .003) and monocytopenia (P =.01) at the time of diagnosis of infection were also independently associated with a poor outcome, whereas salvage posaconazole-based therapy (P=.01) and neutrophil recovery (P = .009) were predictive of a favorable outcome. CONCLUSIONS Because discriminating between zygomycosis and aspergillosis in a timely fashion is difficult, the pursuit of aggressive diagnostic strategies and prompt initiation of antifungal agents with activity against Zygomycetes should be considered for patients with hematological malignancy who are at an increased risk for zygomycosis.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.

Background. The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. Methods. Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. Results. Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30–1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12–0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16–0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. Conclusions. Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies

Caspofungin (CAS) as salvage therapy for refractory invasive aspergillosis (IA) had a response rate of 45% among a heterogeneous group of patients. The use of CAS with other agents is appealing given its unique mechanism of action. Therefore, the authors retrospectively evaluated the efficacy and toxicity of CAS plus liposomal amphotericin B (LipoAMB) in patients with documented (definite or probable) or possible IA.

Predictors of Pulmonary Zygomycosis versus Invasive Pulmonary Aspergillosis in Patients with Cancer

BACKGROUND Pulmonary zygomycosis (PZ), an emerging mycosis among patients with cancer, has a clinical manifestation similar to that of invasive pulmonary aspergillosis (IPA). Most cases of PZ in such patients develop as breakthrough infections if treatment with antifungal agents effective against Aspergillus species is administered. However, clinical criteria to differentiate PZ from IPA are lacking. METHODS We retrospectively reviewed the clinical characteristics and computed tomography (CT) findings for 16 patients with cancer and PZ and for 29 contemporaneous patients with cancer and IPA at the time of infection onset (2002-2004). Patients with mixed infections were excluded. Parameters predictive of PZ by univariate analysis were included in a logistic regression model. RESULTS Almost all patients with PZ (15 of 16) and IPA (28 of 29) had underlying hematological malignancies and typical risk factors for invasive mold infections. In logistic regression analysis of clinical characteristics, concomitant sinusitis (odds ratio [OR], 25.7; 95% confidence interval [CI], 1.47-448.15; P = .026) and voriconazole prophylaxis (OR, 7.76; 95% CI, 1.32-45.53; P = .023) were significantly associated with PZ. The presence of multiple (> or = 10) nodules (OR, 19.8; 95% CI, 1.94-202.29; P = .012) and pleural effusion (OR, 5.07; 95% CI, 1.06-24.23; P = .042) at the time that the patient underwent the initial CT were both independent predictors of PZ in the logistic regression analysis of radiological parameters. No difference occurred in the frequency of other CT findings suggestive of pulmonary mold infections (e.g., masses, cavities, halo sign, or air-crescent sign) between the 2 patient groups. CONCLUSIONS PZ in immunocompromised patients with cancer could potentially be distinguished from IPA on the basis of clinical and radiological parameters; prospective validation is needed.

Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001-2007): stable incidence but changing epidemiology of a still frequently lethal infection.

The incidence, epidemiology, Candida species distribution, resistance patterns, and outcome of candidemia in high‐risk hematologic malignancy and/or stem cell transplantation patients have not been extensively described since the introduction of new antifungal agents.

Pharmacology of Systemic Antifungal Agents

Traditionally, many invasive fungal infections were associated with a poor prognosis, because effective therapeutic options were limited. The recent development of new antifungal agents has significantly contributed to the successful treatment of fungal diseases. These drugs offer novel mechanisms of action and expanded spectrums of activity over traditional treatment options. However, with these new agents comes the need for increased awareness of the potential interactions and toxicities associated with these drugs. Therefore, an understanding of the pharmacokinetic and pharmacodynamic properties of the classes of antifungal compounds is vital for the effective management of invasive fungal infections. This review provides a summary of the pharmacologic principles involved in treatment of fungal diseases. The number of agents available to treat invasive fungal infections has increased by 30% since the turn of the millennium. Although that statistic is impressive, it brings the total number of approved systemic antifungal drugs to only 14 [1], with the potential for 1 more product to possibly emerge this year. These recent additions have provided clinicians with a tool previously lacking in the management of these life-threatening infections: therapeutic alternatives. Along with new options, however, comes the need to understand the uniqueness of each agent, including its role in therapy, toxicity profile, and interactions with concomitant medications. To attain the maximum effect from these agents, clinicians should also become familiar with strategies to optimize efficacy through an understanding of pharmacokinetic and pharmacodynamic properties. These characteristics are unique for each class of antifungal drug and even for each member within a class. In many cases, this variability is not subtle and merits careful attention.

Influence of Test Conditions on Antifungal Time-Kill Curve Results: Proposal for Standardized Methods

ABSTRACT This study was designed to examine the effects of antifungal carryover, agitation, and starting inoculum on the results of time-kill tests conducted with various Candida species. Two isolates each of Candida albicans, Candida tropicalis, and Candida glabrata were utilized. Test antifungal agents included fluconazole, amphotericin B, and LY303366. Time-kill tests were conducted in RPMI 1640 medium buffered with morpholinepropanesulfonic acid (MOPS) to a pH of 7.0 and incubated at 35°C. Prior to testing, the existence of antifungal carryover was evaluated at antifungal concentrations ranging from 1× to 16× MIC by four plating methods: direct plating of 10, 30, and 100 μl of test suspension and filtration of 30 μl of test suspension through a 0.45-μm-pore-size filter. Time-kill curves were performed with each isolate at drug concentrations equal to 2× MIC, using a starting inoculum of approximately 105 CFU/ml, and incubated with or without agitation. Last, inoculum experiments were conducted over three ranges of starting inocula: 5 × 102 to 1 × 104, >1 × 104 to 1 × 106, and >1 × 106 to 1 × 108 CFU/ml. Significant antifungal carryover (>25% reduction in CFU/milliliter from the control value) was observed with amphotericin B and fluconazole; however, carryover was eliminated with filtration. Agitation did not appreciably affect results. The starting inoculum did not significantly affect the activity of fluconazole or amphotericin B; however, the activity of LY303366 may be influenced by the starting inoculum. Before antifungal time-kill curve methods are routinely employed by investigators, methodology should be scrutinized and standardized procedures should be developed.

Pharmacodynamics of Caspofungin in a Murine Model of Invasive Pulmonary Aspergillosis: Evidence of Concentration-Dependent Activity

BACKGROUND A paucity of data exists regarding the pharmacodynamics of caspofungin (CAS) during invasive pulmonary aspergillosis (IPA). We conducted a dosage-fractionation study to characterize the in vivo pharmacodynamics of CAS activity during IPA, using immunosuppressed mice inoculated intranasally with Aspergillus fumigatus. METHODS After single intraperitoneal doses (0.25, 1.0, and 4.0 mg/kg), plasma CAS concentrations were assayed by high-performance liquid chromatography. The pharmacokinetic data were analyzed by nonparametric population pharmacokinetic analysis. Three dosage groups (0.25, 1.0, and 4.0 mg/kg) fractionated into 3 different dosing intervals (q6, q24, or q48 h) were then used to evaluate the pharmacokinetic/pharmacodynamic effects (percentage of time greater than the minimum effective concentration [MEC], 96-h area under the plasma concentration curve:MEC ratio, and peak concentration in plasma [Cmax]:MEC ratio) at clinically achievable exposures. Mice were treated for 96 h and were then euthanized, and their lungs were harvested for analysis of pulmonary fungal burden by real-time quantitative polymerase chain reaction. RESULTS A concentration-dependent reduction in mean pulmonary fungal burden was evident in mice in the 1 mg/kg dosage-fractionation group, with significantly lower mean pulmonary fungal burden in mice dosed q48 h versus q6 h (P < .01). A paradoxical increase in pulmonary fungal burden was observed in the highest dosage-fractionation group. CONCLUSIONS CAS demonstrates concentration-dependent pharmacodynamics in the treatment of IPA. The Cmax : MEC ratio appears to be the parameter most closely associated with the reduction of pulmonary fungal burden.