Multidisciplinary approach to the treatment of invasive fungal infections in adult patients. Prophylaxis, empirical, preemptive or targeted therapy, which is the best in the different hosts?

Figures & data

Figure 1 Different antifungal strategies for treatment in invasive fungal infections based on diagnostic stage.

Table 1 Usual susceptibility patterns for yeasts and moulds

Species	Amphotericin B	Fluconazole	Itraconazole	Voriconazole	Posaconazole	Echinocandins
C. albicans	S^a	S	S	S	S	S
C. tropicalis	S	S	S	S	S	S
C. parapsilosis	S	S	S	S	S	Sb
C. glabrata	S, R	SDD, Rc	SDD, Rd	Sb	Sb	S
C. krusei	S, R	R	SDD, Rd	Sb	Sb	S
C. lusitaniae	S, Re	S	S	S	S	S
C. guilliermondii	S, R	S, SDD	S	S		S
C. dubliniensis	S, Rb	S, SDD, R	S	S		S
Trichosporon spp.	S, R	S, SDD, R	S, SDD	S		R
Blastoschizomyces	S, R	S, SDD, R	S, SDD	S		R
Malassezia spp.	S, R	S	S	S		ND
Rhodotorula spp.	S	S, SDD	S, SDD	S, SDD		R
Cryptococcus spp.	S	S, SDD	S	S	S	R
A. fumigatus	S	R	S, R	S	S	S
A. terreus	R	R	S	S	S	S
A. niger	S	R	S	S	S	S
A. flavus	S	R	S	S	S	S
Fusarium solani	R	R	R	S	S	R
S. apiospermum	R	R	R	S	S	S
S. prolificans	R	R	R	R	R	R
Zygomycetes	S	R	R	R	S	R

^a Notes:S, susceptible; I, intermediate; R, resistant; SDD, susceptibility depends on the dose; ND, no data.

^b Susceptible, but few clinical data are available.

^c 10%–15% of C. glabrata isolates are resistant to fluconazole.

^d Resistant to itraconazole ~50% and ~30% of C. glabrata and C. krusei isolates, respectively.

^e 20% of isolates are resistant to amphotericin B.

Table 2 Antifungal therapy strategies in ICU patients

	Strategy	Antifungal agent	References
Prophylaxis	No generally recommended. Patients with upper gastrointestinal perforation, heavy Candida colonization or with severe acute pancreatitis might be benefited	Fluconazole	Pelz et al 2001; Garbino et al 2002; De Waele et al 2003; Piarroux et al 2004
Empirical	Use of “Candida score” or the Ostrosky-Zeichner prediction rule	De-escalation therapy (*), the choice of antifungal drug must be based on the individual characteristics of the patient	Leon et al 2006; Ostrosky-Zeichner et al 2007
Pre-emptive	Based on detection of galactomannan, (1,3)-β-d-glucan or C. albicans germ tube antibodies	De-escalation therapy (*), the choice of antifungal drug must be based on the individual characteristics of the patient	Ostrosky-Zeichner et al 2005; Zaragoza et al 2006; Meersseman et al 2008
Targeted	Based on sterile site culture results	De-escalation therapy (*), the choice of antifungal drug must be based on the individual characteristics of the patient (**)	Rex et al 1994; Phillips et al 1997; Mora-Duarte et al 2002; Kullberg et al 2005; Zaragoza and Peman 2006; Kuse et al 2007; Pappas et al 2007

* Notes:An early broad-spectrum antifungal agent is initially prescribed, switching to a narrower-spectrum drug (fluconazole) when mycological identification and susceptibility studies are provided.

** Focus on the presence of renal or hepatic failure, hemodynamic instability and possible interactions with other drugs.

Table 3 Antifungal therapy strategies in hematological patients

	Strategy	Antifungal agent	References
Prophylaxis	High risk patients*:	Itraconazole or Posaconazole or Voriconazole	Jarque et al 2004; Marr et al 2004b; Cornely et al 2007b; Ullmann et al 2007; Wingard et al 2007
	Intermediate risk patients**:	Fluconazole
Empirical	Severely neutropenic cancer patients with persistent or relapsing fever despite broad-spectrum antibacterial therapy	Liposomal AmB or Caspofungin	Hughes et al 2002; Walsh et al 1999, ^Citation2004
Pre-emptive	Based on GM assays or CT or bronchoscopic cultures	Liposomal AmB or Caspofungin or Voriconazole	Maertens et al 2005
Targeted	Based on sterile site culture results	Voriconazole Combination therapy	Herbrecht et al 2002; Marr et al 2004a; Caillot et al 2007

* Notes:Acute leukemia patients, Allogenic HSCT recipients, autologous HSCT recipients, previous episode of IFI, rescue chemotherapy for acute leukemia patients and severe aplastic anemia.

** Autologous HSCT recipients, acute linfoblastic leukemia, rescue therapy for myeloma and lymphomas.

Table 4 Antifungal therapy strategies in lung transplantation (LT) recipients

	Strategy	Antifungal agents	References
Prophylaxis	Generally recommended in the postoperative period	Voriconazole or Amphotericin B (intravenous or aerosolized)	Calvo et al 1999; Monforte et al 2005; Husain et al 2006a; Drew 2006; Lowry et al 2007
Pre-emptive	Patients with pre- and/or post-transplant fungal airway colonization Patients with chronic rejection and respiratory samples positive for Aspergillus, mainly in single LT patients Detection of galactomannan antigen of Aspergillus, (1,3)-β-d-glucan or C. albicans germ tube antibodies are not reliable methods with usefulness sufficiently demonstrated in the LT	Voriconazole or Amphotericin B (intravenous or aerosolized)	Singh and Husain 2003; Sole et al 2005
Targeted	Based on sterile site culture results or non-absolutely sterile samples (respiratory specimens) processed by semi or quantitative methods and considered clinically significant AND/OR Based in histological studies of biopsies and other clinical specimens obtained by instrumental or chirurgic procedures (respiratory and non-respiratory samples)	Voriconazole or Amphotericin B or Echinocandins Combination therapy (triazole plus echinocandin) in those patients with LT and renal failure or infected by A. fumigatus	Herbrecht et al 2002; Singh et al 2006a

Table 5 Antifungal therapy strategies in recipients of nonpulmonary solid organ transplantation (NP-SOT)

	Strategy	Antifungal agents	References
Prophylaxis	Universal prophylaxis is not recommended Antifungal prophylaxis adapted-to-risk is reasonable High-risk NP-SOT recipients need to be identified in order to prevent the development of IFI	Oral prophylaxis with nonabsorbable antifungal agents (nystatin, clotrimazole, amphotericin B) has shown inconsistent results. Azoles (fluconazole, itraconazole) or Amphotericin B (lipid formulations) or Echinocandins (caspofungin)	Lumbreras et al 1996; Winston et al 1999; Singh et al 2001; Winston and Busuttil 2002; Fortun et al 2003, ^Citation2007; Sharpe et al 2003; Hellinger et al 2002, ^Citation2005; Munoz et al 2004; Castroagudin et al 2005
Pre-emptive	Strategy not sufficiently validated in these patients Detection of galactomannan antigen of Aspergillus, (1,3)-β-d-glucan or C. albicans germ tube antibodies are not usefulness in NP-SOT recipients	Azoles or Amphotericin B	Akamatsu et al 2007; Perkins 2007
Targeted	Based on sterile site culture results or nonabsolutely sterile samples (respiratory specimens) processed by semi or quantitative methods and considered clinically significant AND/OR Based in histological studies of biopsies and other clinical specimens obtained by instrumental or chirurgic procedures (respiratory and non-respiratory samples)	Azoles or Amphotericin B or Echinocandins Combination therapy (triazole plus echinocandin) in patients with SOTand renal failure or infected by A. fumigatus	Herbrecht 2002; Singh et al 2006a

Table 6 Etiological and clinical characteristics of IFI according to the type of SOT

Type of transplant	Incidence of IFI (%)	Usual etiologic agent (s)	Variables portending higher risk of IA	Mortality(%) of IA
Renal	0–20	76%–95% Candida (mainly urinary tract infections), 0%–25% Aspergillus	Graft failure requiring hemodialysis, high level and prolonged duration of corticosteroids	77
Heart	5–20	70%–90% Aspergillus, 8%–25% Candida	Isolation of Aspergillus species in respiratory tract cultures, reoperation, post-transplant hemodialysis, CMV disease	78
Liver	5–40	35%–0% Candida, 9%–45% Aspergillus	Retransplantation, renal failure (particularly requiring renal replacement therapy), fulminant hepatic failure as an indication for transplantation, primary allograft failure, high transfusion requirements, use of monoclonal antibodies,	87
Lung/Heart–Lung	10–45	43%–72% Candida, 25%–50% Aspergillus	Single lung transplant, CMV infection, rejection and augmented immunosuppression, obliterative bronchitis, Aspergillus colonization, acquired hypogammaglobulinemia, presence of bronchial stents, reperfusion injury, airway ischemia	68
Pancreas (+kidney)	10–40	>90% Candida, 0%–3% Aspergillus	Similar factors to the liver and kidney transplant, graft lost (vascular graft thrombosis, post-reperfusion pancreatitis), enteric drainage, alemtuzumab-containing immunosuppresive regimen	100
Small bowel	30–60	80%–100% Candida, 0%–5% Aspergillus	Not clearly determined, similar factors to others intraabdominal SOT recipients; Graft rejection/dysfunction, enhanced immunosuppression, anastomotic disruption, multi-visceral transplant	66

Abbreviations: SOT, solid organ transplantation/solid organ transplant recipients; IFI, invasive fungal infection; IA, invasive aspergillosis; CMV, cytomegalovirus.

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