Candidemia
Hospital-acquired infections frequently cause morbidity and mortality.
Candida bloodstream infections are a good example; they are the fourth most common cause overall of hematogenous infections in the United States, and they rank fourth to seventh in Europe [
1,
52]. In multicenter studies conducted in Brazil and in Mexico, it has been found that 4% of nosocomial bloodstream infections are caused by
Candida species [
53‐
55].
C. albicans is the most frequently isolated yeast worldwide. In the United States,
C. glabrata is the second, but in Latin America,
C. tropicalis and
C. parapsilosis are the most important species after
C. albicans [
54,
56].
C. tropicalis is usually isolated from neutropenic patients and other immunocompromised hosts, perhaps because of the extensive use of prophylactic fluconazole in the region.
C. parapsilosis has been associated with central venous catheter infections because of its ability to form biofilms, and it has been a significant pathogen in neonatal intensive care units [
2•,
54,
56], even more important than
C. albicans [
57‐
61].
The incidence of bloodstream fungal infections is 0.28 to 0.96 per 1,000 admissions in the United States and 0.2 to 0.38 in Europe, whereas in Latin America these rates vary between 1.2 and 5.3 (0.2–0.5 cases per 1,000 patient-days) [
1,
2•,
54,
55,
57]. Preliminary data in two referral centers in Mexico City showed an incidence rate of 2.8 cases per 1,000 hospital discharges, which corresponded to 0.38 per 1,000 patient days (Table
1) [
53].
Table 1
Candidemia in Latin America: Recent case series and clinical surveillance studies
Brazil
|
| MOPS | 712/11 |
C. albicans 41% | 4 cities in Brazil/2003–4 | 54% | 2.49 (0.37) | 1% to FCZ |
C. tropicalis 20.9% |
C. parapsilosis 20.5% |
| MOPS | 282/4 |
C. albicans 38% | Sao Paulo/2002–3 | 61% | 1.6 | 2% to FCZ (C. glabrata, C. rugosa) |
C. parapsilosis 23% |
C. tropicalis 17% |
Bruder-Nascimento et al. [ 57] | SOPS | 102/1 |
C. albicans 32.4% | Sao Paulo/1998–2005 | | | 14.6% to FCZ (C. glabrata 68%) |
C. parapsilosis 48% |
C. guilliermondii 6.9% |
Mexico
|
| MOPS | 5/398 |
C. parapsilosis 37.9% | Monterrey/2004–7 | | | 2.4% to FCZ (31% C. glabrata) |
C. albicans 31.9% |
C. tropicalis 14.8% |
C. glabrata 8% |
Hernández-Dueñas et al. [ 62] | SORS | 1/112 |
C. albicans
| México D.F/1992–2007 | 63% | | 1.8% to FCZ (C. glabrata 40%) |
C. tropicalis
|
C. parapsilosis
|
| MOPS | 2/74 |
C. albicans 45.9% | México D.F/2008–10 | 46% | 2.8 (0.38) | |
C. tropicalis 25.7% |
C. glabrata 13.5% |
Colombia
|
Diaz-Granados et al. [ 59] | CC | 1/18 |
C. albicans 38.9% | Bogotá/2004 | 33% | (0.25–1.1) | |
C. parapsilosis 16.7% |
C. glabrata 5.5% |
C. tropicalis 5.5% |
| MOPS | 195 |
C. albicans 41.8% | Medellín/2001–7 | | | 9.5% to FCZ (18.8% C. glabrata, C. parapsilosis 14.9%, C. krusei 100%, C. guilliermondii 50%, C. famata 50%) 3.6% to VOR (C. glabrata 15.6%, C. krusei 18.2%). |
C. tropicalis 22.9% |
C. parapsilosis 19.9% |
| MOPS | 1, 622/27 |
C. albicans 44.7% | Colombia/2001–7 | | | |
C. parapsilosis 13.6% |
C. tropicalis 13.6% |
Venezuela
|
| MOPS | 74/1 |
C. parapsilosis 29.7% | Maracaibo/2000–2 | | | 2.7% intermediate to FCZ (C. glabrata, C. parapsilosis). |
C. tropicalis 27% |
C. albicans 28% |
| MOPS | 33/15 |
C. albicans 9.1% | Venezuela/2006–7 | | | 6% to FCZ (C. krusei 100%, C. tropicalis 3%, C. glabrata 9%) |
C. parapsilosis 48.5% |
C. tropicalis 21.2% |
Argentina
|
| SORS | 1/ |
C. parapsilosis 32.6% | Buenos Aires/2001–3 | 20.8% | | |
C. albicans 26.5% |
C. tropicalis 24.5% |
Chile
|
| SOPS | 1/22 |
C. albicans 44.4% | Chile/2001–3 | 16.6% | | No resistance to FCZ in C. albicans
|
C. tropicalis 27.7% |
C. glabrata 11% |
Crude mortality rates of about 40% have been reported worldwide; in reports from Brazil, Mexico, Argentina, Chile, Colombia, and Costa Rica, the mortality rates vary between 20% and 63% [
53,
54,
59,
62‐
64]. Lower mortality rates have been reported in outbreaks caused by
C. parapsilosis [
60,
63], but this rate seems to vary between different age groups: 24% to 34% in neonatal intensive care units; 43% in children less than 1 year old; 23% in children 1–12 years of age; and 40% to 63% in adults (Table
1) [
53,
54,
60,
65].
In Latin America, amphotericin B desoxycholate continues to be the antifungal drug most commonly used, followed by fluconazole [
54,
55,
62,
66,
67]. Echinocandins and other amphotericin B formulations are rarely used because of their higher cost.
Antifungal resistance studies have been conducted globally and regionally. Overall resistance to FCZ varies between 1% and 6%. However, when analyzed by species, resistance to fluconazole in
C. albicans, C. parapsilosis and
C. tropicalis is less than 3% [
54,
55,
58,
60‐
63]. Resistance to fluconazole in
C. tropicalis has been reported in up to 6% to 8% of cases, but these results could be influenced by “the trailing phenomenon” seen in susceptibility testing.
C. glabrata and
C. krusei are usually more resistant (30% and 70%, respectively) [
58,
67,
68]. In these large studies, resistance to amphotericin B, echinocandins, or voriconazole has not been found [
69••].
Cryptococcosis
Cryptococcosis is caused by a complex group of basidiomycetes, usually yeasts of 2–10 mm in diameter. This complex is called
Cryptococcus neoformans and is divided in two varieties:
C. neoformans var
neoformans (serotypes A and D, genotypes VNI–IV) and
C. neoformans var
gattii (serotypes B and C, genotypes VGI–IV). About 95% of cases are caused by var
neoformans, and serotype A (var
grubii) is responsible for 95% of those. This pathogen has ubiquitous distribution.
C. gattii is endemic in tropical and subtropical regions, and is usually observed in immunocompetent individuals [
70].
Cryptococcosis is the most important cause of fungal meningoencephalitis worldwide, affecting immunocompetent as well as immunocompromised individuals. It may cause other clinical patterns, such as fungemia, pneumonia, and lesions of bone, skin, and soft tissue. Meningoencephalitis is the most common clinical form of cryptococcosis in Latin America, with 85% of cases caused by
C. neoformans [
71]; 80% are associated with HIV infection [
72,
73].
More than 215,000 patients with AIDS and cryptococcosis were observed between 1980 and 2002, and 60% of the patients were concomitantly diagnosed [
72]. The prevalence of meningitis in Mexico has been about 7% to 11% in patients with HIV, with a decreasing trend in recent years [
2•]. Some studies reported
Cryptococcus to be the fourth or fifth most common yeast isolated in blood cultures; sometimes it is even more common than
C. glabrata [
28••,
60].
The incidence of cryptococcal meningitis varies according to the population being studied. In Rio de Janeiro, the incidence was 0.3/100,000 inhabitants in 2002, increasing to 0.68 in 2003 [
73]. In Colombia, this rate was determined to be 0.24/100,000 inhabitants among the general population, but 3/1,000 in HIV patients [
74].
A multicenter Ibero-American study done in 2003 collected 340 strains derived from humans, animals, and soil and found that
C. neoformans var
grubii (serotype A) was the most common species (56% to 93.3%). The VNI genotype was the most common in Mexico, Guatemala, Venezuela, Brazil, Colombia, Peru, Chile, and Argentina (45% to 93.3%).
C. neoformans var
gattii was isolated in 3% to 41%, and the VGI and VGIII genotypes were the most frequent. Of note, genotypes VNIV and VGII were not identified in Mexico in this study, but a later report found these genotypes in two isolates from Mexico (Table
2) [
28••,
71,
75].
Table 2
Cryptococcosis in Latin America: Recent clinical and molecular epidemiologic surveillance studies
| Colombia | 788 |
C. neoformans 95.9% | Serotype A 95.9% | 621 AIDS patients, 167 non-AIDS | FCZ: C. neoformans (n = 84), 100%; C. gattii (n = 9), 88.8% |
C. gattii 3.8% | Serotype B 3.3% |
| Serotype C 0.5% |
| Serotype D 0.3%. |
| Venezuela | 132 |
C. neoformans 90.9% | Serotype A 59.8% | | |
C. gattii 9.1% | Serotype D 25.8% |
| Brazil | 124 | C. neoformans 96.7% | Serotype A 96.7% (100% VNI) | 84 AIDS patients, 35 pigeon excreta | |
C. gattii 3.3% | Serotype B 3.3% (100% VGIII) |
| Brazil | 123 |
C. neoformans 89.6% | | AIDS and non-AIDS | |
C. gattii 10.4% |
| Brazil | 443 |
C. neoformans 72% | VNI 64%, VNII 5%, VNIV 3% | | |
C. gattii 28% | VGII 21%, VGIII 4%, VGI 3% |
| Mexico | 72 |
C. neoformans 87.5% |
C. neoformans (n = 63): VNI 87%, VNII 7.9%, VNIII 4.7% | | AMB: 100% |
C. gattii 12.5% |
C. gattii (n = 9): VGI 22%, VGII 22%, VGIII 22% |
Most cryptococcosis cases (75–95%) occur in HIV-infected young men (<40 years old) [
75‐
77]. In this subgroup,
C. neoformans var
grubii genotype VNI has been the most frequent pathogen isolated, and most of the patients show counts below 100 CD4+ cells [
71,
74,
76‐
78].
da Cunha Colombo et al. [
73] reported 81 HIV-infected patients with cryptococcosis; 50% died before receiving highly active antiretroviral therapy (HAART), and among those who received treatment, 25% showed signs of immune reconstitution syndrome (IRIS), and 33% of the latter group died. Cryptococcosis is the second most frequent cause of death as a result of a fungal infection in Latin America. Mortality rates in Africa and Latin America are unacceptably high (31% to 75%) when compared with 20% in developed nations. Alcoholism and high lactate dehydrogenase (LDH) levels (> 400 U/L) have been found to be significant risk factors for death [
47,
72,
73,
78,
79].
Patients without HIV infection usually have other immunosuppressive conditions that predispose them to this infection. The immunosuppression in these cases has been attributed to defects in the cellular immune response as part of the disease or conditioned by immunosuppressive therapy, as seen in patients with systemic lupus erythematosus, transplant recipients, and patients with malignancies who are undergoing chemotherapy [
73]. However, recent reports have found no underlying disease in 5–10% of the patients with cryptococcosis; this situation may delay diagnosis and treatment and worsen the outcome [
74,
76,
77].
Antimicrobial susceptibility surveillance studies have shown that more than 99% of the isolates are susceptible to amphotericin B, fluconazole, and flucytosine. Pfaller et al. [
80] analyzed 1,811 isolates from five different geographic regions and showed that isolates from Latin America had results similar to those from other regions.
Lizarazo et al. [
74] reported susceptibility of 93 strains between 1997 and 2005, finding that more than 97% of them were susceptible to amphotericin B. He also found that isolates of
C. neoformans var
grubii were 100% susceptible to fluconazole and itraconazole, but
C. gattii isolates were only 88% susceptible to these agents.
Current treatment guidelines for cryptococcal meningoencephalitis recommend the use of amphotericin B desoxycholate plus flucytosine, but in Latin America, 80% of patients are treated with amphotericin B desoxycholate and fluconazole, with results similar to those of the standard treatment [
76‐
78].
Infection by Aspergillus and Other Filamentous Fungi
IFIs caused by
Aspergillus species
, Fusarium, Mucormycosis,
Scedosporium,
Trichosporon,
Rhodotorula,
Alternaria,
Bipolaris, and
Curvularia have been extensively described in patients with hematologic neoplasias, transplant recipients (especially bone marrow transplants), persons living with diabetes, and patients under chronic high-dose steroid treatment. In Latin America, IFIs have been described that were caused by this group of pathogens, especially
Candida and
Aspergillus (>90% of the cases). In the same group of patients, the more relevant risk factors were profound neutropenia, monocyte count less than 100 cells for more than 4 days, and elevated serum level of reactive protein C [
81].
In patients with profound neutropenia and fever, up to 7% of the cases are caused by an IFI. After candidemia, the most important pathogens involved are
Aspergillus spp,
Fusarium spp, and mucormycosis agents. In Latin America, bronchopulmonary aspergillosis has been reported as the third leading cause of deep mycosis, and mucormycosis as the eighth most common cause in some general hospitals [
82], [
83•,
84]. Characteristically, diagnosis can only be established by histopathologic findings such as angioinvasion or by the isolation of these pathogens from the bloodstream.
Aspergillosis
Candida spp and
Aspergillus spp are responsible for 80% to 90% of all IFIs. A large amount of knowledge about
Aspergillus has been accumulated recently, especially regarding its biology, epidemiology, risk factors for infection, host characteristics, clinical pictures (acute invasive sinusitis, allergic sinusitis, pulmonary invasive aspergillosis, allergic bronchopulmonary aspergillosis, aspergillomas, intestinal and cutaneous aspergillosis), treatment, and preventive strategies. Studies have considered all types of patients, but most have emphasized patients with hematologic neoplastic diseases or bone marrow transplant recipients.
Aspergillus is the most common cause of IFI in patients with allogenic HSCT in Latin America, with a bimodal distribution (before posttransplant day 30 or after day 90), and it is the second most common cause in solid-organ transplant recipients. Aspergillosis occurs in 3% of patients with bone marrow transplants and in 1.3% of hepatic transplants, rates higher than the reported incidence in surveillance studies in the United States and Europe [
5‐
7]. The most common species is
A. fumigatus, and the most common clinical presentation is pulmonary, followed by sinusitis [
81,
85,
86].
Diagnostic tools that have been implemented include culture, histopathology, and serologic methods; galactomannan in serum by immunoenzymatic assays has proven to be useful when determined in multiple serial samples in several circumstances, including early diagnosis in probable invasive infection (with concomitant improvement in outcome), and therapeutic follow-up to monitor treatment efficacy [
85,
87,
88]. Recently, several institutions in Latin America have incorporated its use for the routine evaluation of high-risk patients.
Voriconazole is considered the first-line treatment for this clinical condition, but amphotericin B desoxycholate is still used in Latin America because of economic reasons.
Crude mortality from aspergillosis ranges from 30% to 83% worldwide, and mortality rates in Latin America are higher than 70%, especially among HSCT recipients. Mortality in solid-organ transplant recipients is lower than in HSCT recipients worldwide [
5‐
7,
87,
88].
Antimicrobial susceptibility testing in 50 clinical isolates of
A. fumigatus (from México, Peru, Argentina, and France) showed a splendid susceptibility to itraconazole (MIC
90 = 0.25 mg/mL), voriconazole (MIC
90 = 0.25 mg/mL), and amphotericin B (MIC
90 = 1 mg/mL), similar to other results from two recent international studies [
89,
90].
Fusariosis
One of the most common mold IFIs seen in immunocompromised patients is caused by
Fusarium spp septated fungi. Three clinically important species have been recognized:
F. solani,
F. oxysporum, and
F. verticillioidis. These IFIs are therapeutic challenges worldwide because
Fusarium spp are often resistant to most antifungal agents. Fusariosis causes fungemia (>60%) in immunocompromised patients, with or without endocarditis, skin lesions (60–80%), sinusitis, and lung disease. In immunocompetent patients, fusariosis tends to be a superficial infection (keratitis and onychomycosis) or to cause locally invasive skin or soft-tissue infection [
91].
Brazilian investigators reported an overall incidence of 5.97 cases per 1,000 HSCT recipients; HLA-mismatched related-donor HSCT recipients showed the highest incidence and autologous HSCT recipients, the lowest. A trimodal distribution of fusariosis (early, late, and >1 year after receipt of HSCT) has been described, and Fusarium is well known as the second most important invasive filamentous fungi in immunocompromised hosts.
The crude mortality rate reported in Latin America is 66%, but in patients with disseminated disease and persistent immunodeficiency (as in prolonged neutropenia and monocytemia and chronic high doses of corticosteroid), mortality is as high as 100%; similar results were reported in the Transplant-Associated Infection Surveillance Network (TRANSNET) database [
5,
6,
92,
93].
Management of this IFI depends on accurate identification. The first line of therapy is high-dose amphotericin B desoxycholate (>1.5 mg/kg per day). Voriconazole can be used as a second choice, and posaconazole and other antifungal combinations have been described as salvage therapy in cases of invasive fusariosis. Adjunctive treatment is based on identification of cases requiring surgical debridement and patients who can tolerate less immunosuppressive therapy as well as granulocyte colony-stimulating factors [
94].
Mucormycosis
Caused by hyaline aseptate fungi, the most common species are Mucor, Rhizopus, Rhizomucor, and Lichtheimia (previously Absidia), although Cunninghamella Bertholletia and Apophysomyces elegans also are frequent causes.
Multicenter studies have described an increase in the incidence of mucormycosis, which has become the third leading cause of IFI among high-risk immunocompromised patients, after
Aspergillus and
Fusarium. Major risk factors for mucormycosis include profound and prolonged neutropenia and chronic high-dose corticosteroid use, as well as tissue iron overload, uncontrolled diabetes, hypertriglyceridemia, voriconazole prophylaxis (mainly in HSCT), or previous skin and soft-tissue trauma [
8,
95]. The most commonly seen clinical forms are rhinocerebral, pulmonary, osteomuscular and skin diseases.
Some clinical reports and brief series of cases in Latin America have been published, all of which share the same characteristics: late diagnosis, biopsy as the main tool in diagnosis, and high mortality rate. The mortality rate has decreased with the use of combined therapy using antifungal drugs and extensive surgical debridement [
95‐
103].