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MEDICAL FRONTIERS - 21st European Congress of Clinical Microbiology and Infectious Diseases/ 27th International Congress of Chemotherapy

Milan, Italy / May 7-10, 2011

Candida and Aspergillus spp. are the most common causes of invasive fungal infection (IFI) in the intensive care unit (ICU). Invasive aspergillosis (IA) is a significant cause of complications and mortality among hospitalized patients, especially among immunocompromised patients in the hematology setting and ICU patients. Invasive candidiasis infections, also associated with considerable morbidity and mortality, increase the duration of ICU and hospital stays, thereby increasing total costs.

Managing patients with suspected fungal infections poses many challenges, including the degree of certainty of the diagnosis required to initiate treatment and selection of the appropriate antifungal agent. Early diagnosis of IFI is difficult but delayed treatment increases mortality.

Debate Over Pre-emptive Therapy

Although consensus guidelines recommend empiric therapy as a standard of care for persistent or relapsing fever during neutropenia, solid evidence that it reduces mortality related to fungal infection is lacking. However, many cases of nonfungal fever result in overtreatment with the use of empiric therapy, and the empiric strategy using newer antifungal drugs is expensive.

New noninvasive methods for the diagnosis of IFI may permit a pre-emptive approach with the objectives of decreasing the number of patients treated compared with the fever-driven empiric approach by treating only true cases of IFI but before overt IFI, and reducing costs and toxicity of therapy. The risks of pre-emptive strategy are potentially more deaths and more IFIs.

Because ambiguity often surrounds the diagnosis of IFIs, pre-emptive antifungal therapy based on clinical signs, before microbiologic confirmation of disease, “is a realistic approach to management of patients in whom IFI is strongly suspected,” argued Dr. Peter J. Donnelly, Department of Haematology, Radboud University Nijmegen Medical Centre, The Netherlands, here at ECCMID/ICC.

A prospective feasibility study of a protocol-driven pre-emptive approach of 136 high-risk treatment episodes for patients at risk of acquiring IFIs (i.e. receiving chemotherapy for acute leukemia or myelodysplastic syndrome, or those undergoing allogeneic hematopoietic stem cell transplantation [HSCT]) was performed by Maertens et al. (Clin Infect Dis 2005;41(9):1242-50). Patients were screened for the presence of galactomannan and underwent a diagnostic evaluation that included a high-resolution computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage. Blood cultures were obtained daily from patients on steroids. Neutropenic fever developed in 117 episodes, 58 of which qualified for empiric antifungal therapy. The rate of antifungal use for neutropenic episodes with the protocol-driven approach was reduced from 35% to 7.7%. Overall mortality was 18.1%; IA was the primary cause of death in 2 patients. Autopsies were performed on all patients who died, and no cases of IA were missed with the pre-emptive strategy.

Empiric therapy was compared with pre-emptive therapy in 293 patients with hematologic malignancies who were receiving chemotherapy or autologous HSCT (Clin Infect Dis 2009;48:1042-51). The pre-emptive therapy triggers were the same ones as those used in the Maertens study. Empiric therapy was driven by persistent or recurrent fever despite antibacterial treatment.

Survival at study completion was 97.3% in the empirically treated group and 95.1% in the pre-emptive group. The rates of antifungal therapy were 66% in the empiric arm vs. 46% in the pre-emptive arm. The secondary end point of IFI was 9.1% in the pre-emptive treatment arm vs. 2.7% in the empiric treatment arm; IFI-related mortality was 2.1% vs. 0% in the pre-emptive and empiric arms, respectively (Figure 1).

The findings suggest that a pre-emptive strategy is feasible and decreases the use of antifungal therapy compared to empiric treatment at a risk of an increased occurrence of IFI, stated Dr. Donnelly. However, the pre-emptive approach has the potential for early therapy in the absence of fever, which would be missed by a fever-driven empiric approach.

IA in Patients with Hematologic Malignancies

A reduction in mortality in patients with hematologic malignancies despite a steady incidence of aspergillosis has coincided with new antifungal treatment options. “A revolution occurred in 2002 with the introduction of voriconazole,” Prof. Livio Pagano, Department of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy, told delegates. In a study evaluating primary therapy of IA (N Engl J Med 2002;347:408-15), patients randomized to voriconazole had significantly better survival at 12 weeks (70.8% vs. 57.9% with amphotericin B; P=0.02) and a higher rate of successful outcomes. Nivoix et al. (Clin Infect Dis 2008;47(9):1176-84) also found that its use as first-line therapy was a factor associated with overall and attributable survival in IA, and as primary therapy it was a prognostic factor associated with survival in IA following HSCT.

In the AmBiLoad trial of immunocompromised patients (Clin Infect Dis 2007;44(10):1289-97), 3 mg/kg of liposomal amphotericin B (L-Amb) as first-line therapy for IA was associated with a response rate of 50% and survival rate of 72% at 12 weeks; no further benefit was offered with the high 10 mg/kg loading dose.

Figure 1.

Caspofungin is a newcomer in the armamentarium for IA, noted Prof. Pagano, “but it’s hard to say that caspofungin is front-line.” In clinical trials of hematologic patients, complete response rates were low. In allogeneic HSCT patients with mycologically documented IA, no patients had a complete response and 42% of patients had a partial response at the end of therapy, and 33% had a complete or partial response at week 12 (Herbrecht et al. Bone Marrow Transplant 2010;45:1227-33).

In guidelines by cooperative groups and international societies (e.g. Infectious Diseases Society of America [IDSA], European Conference on Infections in Leukaemia [ECIL]), voriconazole is the main drug recommended as primary treatment of IA and if it is not available, “L-Amb is only an alternative,” Prof. Pagano told delegates. Many effective options exist for salvage therapy, including caspofungin, posaconazole, voriconazole, L-Amb, ABLC and itraconazole, he stated.

Following IDSA or ECIL guidelines for the treatment of IA in patients with acute myeloid leukemia results in superior rates of clinical success. Prof. Pagano and colleagues (J Antimicrob Chemother 2010;65:2013-8) showed a treatment success rate of 76% with the use of voriconazole or L-Amb as primary therapy, per IDSA guidelines, compared to a treatment success rate of 59% when non-IDSA regimens were used. When voriconazole was used as first-line therapy, per ECIL guidelines, treatment success rate was 84% compared to 63% for
ble 1).

Table 1.

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Although combination therapy of IFIs may offer synergy, its use for primary therapy is not routinely recommended. Regardless, many clinicians use combination therapy outside of the guidelines, Prof. Pagano told delegates.

IA in the ICU

In the ICU setting, the mortality associated with IA is “staggering” at 60% to 90% with proven/probable IA, remarked Prof. Dirk Vogelaers, Departments of General Internal Medicine and Infectious Diseases, University Hospital Ghent, Belgium.

No matter the therapy, diagnostic delay leading to delayed initiation of first-line antifungal therapy accounts for much of the mortality associated with IA. “Problems arise in every component of diagnosis,” he confirmed.

The clinical diagnosis of invasive pulmonary aspergillosis (IPA) has traditionally been based on host factors for acquisition of the disease and microbiologic data. CT imaging of the chest in patients with signs and symptoms suggestive of IPA can identify abnormalities (e.g. halo sign) characteristic of IPA, permitting an upgrade from a “possible” to a “probable” diagnosis, which allows for earlier initiation of therapy, explained Prof. Vogelaers.

Therefore, an Aspergillus-positive respiratory tract sample in an ICU patient should trigger further diagnostic exploration using bronchoalveolar lavage as well as CT scan and pulmonary biopsy, although difficult to achieve, he said.

Candida Species

The incidence of candidemia (C) and other forms of invasive candidiasis (IC) is particularly high in the ICU, where patients often present with multiple organ failure and mortality is higher than average. The ICE (Invasive Candidiasis Intensive Care) study is one of the largest performed to assess the efficacy of an antifungal agent in the high-risk ICU patient population. Details of the open-label study were described by Prof. Markus Ruhnke, Department of Medicine, Charité University, Berlin, Germany.

Patients with documented C/IC received i.v. anidulafungin followed optionally by either oral voriconazole or fluconazole. An echinocandin antifungal, anidulafungin requires no dose adjustment for renal or hepatic impairment and has no known drug-drug interactions, a valuable asset in ICU patients who may be on multiple concomitant drugs, Prof. Ruhnke told delegates.

Patients eligible for the study had signs and symptoms of acute fungal infection within 48 hours prior to the start of the study treatment, and confirmed IC/C within 96 hours before to 48 hours after the start of the study treatment. The 216 patients in the study who received at least 1 anidulafungin dose were enrolled from 60 sites across 19 countries. The mean duration of therapy was 15.9 days.

Some 69.5% of patients in the evaluable modified-intent-to- treat population achieved a global treatment success (i.e. cure or significant improvement in clinical signs/symptoms of C/IC or eradication/presumed eradication of Candida spp.) by the end of treatment. Efficacy was consistent across predefined subpopulations including those with renal insufficiency, hepatic insufficiency, solid tumours, the elderly and those post-abdominal surgery. A successful global response was recorded in 37.5% of patients who had organ transplants. Among the non-neutropenic patients, 71.1% achieved a successful global response.

The Kaplan-Meier survival estimate at day 90 was 53.8%. Treatment-related adverse events (due to anidulafungin and oral azoles) occurred in 15.3% of patients, 1.9% of whom had serious adverse events. “The results of this study support current clinical guidelines that recommend echinocandins as first-line therapy for the treatment of C/IC in moderately to severely ill patients,” confirmed Prof. Ruhnke.

Success and Trough Levels in Lung Transplant Recipients

The relationship between serum concentrations of voriconazole and clinical outcomes has been unclear; insufficient trough concentrations have been reported in treatment failures. New data indicate target serum trough levels should be >1 µg/mL for lung transplant recipients receiving voriconazole prophylaxis.

At the University of Pittsburgh Medical Center, Pennsylvania, 438 serum trough concentrations were measured from 93 lung transplant recipients. Ten per cent of patients developed IFI and 27% had fungal colonization in the respiratory tract during voriconazole prophylaxis. Patients who had trough levels persistently -1 µg/mL were significantly more likely to develop an IFI or become colonized with a fungus than those who achieved at least one level >1 µg/mL, reported Dr. Cornelius Cl
ectious Diseases, University of Pittsburgh (Table 2).

Table 2.

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Despite using standard dosing, a wide range of initial levels was observed (0 to 12.8 µg/mL) and 80% of the patients had significant variation in serial voriconazole levels, noted Dr. Clancy. “In general, increasing the doses, even to 300 mg b.i.d., did not get them above a level of 1 µg/mL,” he said. “About 20% start low and stay low and generally don’t respond to increased doses.” He continued, “We advocate for troughs in the 1 to 4 µg/mL range; our major concern with 4 µg/mL has been more with toxicity than the efficacy that comes with trough levels >1 µg/mL.”

In general, most fungal infections in the transplant population are observed after prophylaxis with voriconazole is stopped, said Dr. Clancy. “We don’t see patients dying of fungal infections the way we once did, and even though we saw more fungal infections with a trough cutoff of 1.5 µg/mL, it’s not like you went from ‘all’ to ‘none’ risk. Even the patients who were really low and developed fungal infections by and large did very well.” In patients with trough levels <1 µg/mL in whom IFIs are a concern, an alternative regimen such as amphotericin B is usually tried, he remarked.

These findings were confirmed by Prof. Haifa Lyster and colleagues, Royal Brompton and Harefield, UK, who determined voriconazole levels in 24 lung transplant recipients, 14 for cystic fibrosis. Trough levels were measured a minimum of 3 to 5 days after starting treatment; a therapeutic level was defined as >1.3 µg/mL.

Forty-two per cent of the patients did not achieve the required target trough level, with no difference between patients with and without cystic - fibrosis. The authors recommended monitoring plasma voriconazole levels to avoid subtherapeutic levels in lung transplant recipients.

Lower Total Resource Use with Longer Prophylaxis

In an economic comparison between voriconazole and itraconazole as primary prophylaxis of IFI after allogeneic HSCT, superior tolerability of voriconazole resulted in a longer duration of prophylaxis and ultimately lower medical resource use and lower costs, revealed clinical researcher Dr. Haran Schlamm, New York City, here at ECCMID-ICC. The analysis was based on an open-label multicentre study in which 665 patients were randomized to receive either antifungal from the day of HSCT for at least 100 days and up to 180 days.

Longer prophylaxis was associated with significantly fewer hospital days (P=0.0110), fewer special unit days (P<0.0001), and lower other azole antifungal use (P<0.0001). Patients who discontinued their prophylaxis were more likely to be re-hospitalized (P=0.0123) and to require ICU admission (P=0.0546) compared to patients without treatment discontinuation.