Fungal diseases Intensivist should know

Abid AlwanMD, JBIM, SF-CCM

Intensive Care Services

Prince Sultan Military Medical City

Muhammad Asim RanaBSc, MBBS, MRCP, MRCPS, FCCP, EDIC, SF-CCM

Department of Critical Care Medicine

King Saud Medical City

Infections rate in ICU

Fungal Diseases

• Yeasts

– Candida

– Cryptococcus

– Environmental Yeast: Histo/Cocci/Blasto

• Molds

– Aspergillus

–Mucor

– Fusarium

Candida Species

• Albicans

Most common if patient not on azole prophylaxis

• Glabrata

Azole resistant strains selected out by azole prophylaxis

• ParaspillosisSkin flora-most often seen in NICU

• Krusei

Inherently resistant to azole

Candida Species

• The clinical manifestations range from local mucous membrane infections to widespread dissemination with multisystem organ failure.

• In the neutropenic host or the severely ill patients, widespread visceral dissemination occurs when Candida species gain access to the bloodstream…… Candidemia !!!

Disseminated candidiasis

• This is frequently associated with multiple deep organ infections or may involve single organ infection.

• Unfortunately, blood cultures are negative in up to 40-60% of patients with disseminated candidiasis.

Disseminated candidiasis

• The history of a patient with presumptive disseminated candidiasis reveals a fever unresponsive to broad-spectrum antimicrobials and negative results from blood culture.

• Physical examination reveals fever (may be the only symptom) with an unknown source and associated sepsis and septic shock.

Terminology

• Candidemia

– Presence of Candida species in the blood.

• Candida in a blood culture should never be viewed as a contaminant and should always prompt a search for the source of infection.

• Invasive Candidiasis

– hematogenous spread to multiple viscera

– (e.g. eye, kidney, heart valves, brain)

Clinical clues

To hematogenous spread of Candida

• Characteristic eye lesions

– chorioretinitis with or without vitritis

• Skin lesions

– appear suddenly as clusters of painless pustules on an erythematous base

• muscle abscesses

EPIDEMIOLOGY

• Fourth most common cause of nosocomial bloodstream infections, accounting for 9 percent of cases in a national survey of United States hospitals from 1995 to 2002

• Most often part of the host's endogenous flora

EPIDEMIOLOGY

• C. albicans is the most common cause of candidemia.

• C. glabrata was responsible for 26 %.• C. parapsilosis 16 percent.• C. tropicalis 8 %• C. krusei 3 %

Knowing the prevalence of the non- albicansCandida species is important because susceptibility to antifungal agents varies among the species

Epidemiology of candidemia

Tortorano Trick Diekema Richet Pfaller Marchetti

(n=569) (n=2759) (n=254) (n=377) (n=1134) (n=1137)

J Hosp Infect CID J Clin Microbiol CMI J Clin Microbiol CID

2002 2002 2002 2002 2002 2004

C.albicans 58,50% 59% 58% 53% 55% 66%

C.glabrata 12,80% 12% 20% 11% 15% 15%

C.parapsilosis 14,60% 11% 7% 16% 15% 1%

C.tropicalis 6,10% 10% 11% 9% 9% 9%

C.krusei 0,90% 1,20% 2% 4% 1% 2%

Miscellaneous 7,10% 7% 2% 6% 1% 7%

Invasive Candidiasis in the ICU

• Common in the ICU (9.8/1000 admissions) with high morbidity (increased LOS ~22 days) & mortality (~ 30-40%) resulting in increased cost (~ $44,000/ episode).

• Difficult to diagnose (cultures positive in only ~ 50%).

Invasive Candidiasis in the ICU

• We can define ICU risk factors for candidiasisand target the population at highest risk with empiric Rx.

• Recent increase in Candida spp. resistant to Diflucan.

• Advances in antifungal therapy have resulted in agents, like – echinocandins and triazoles, with high activity, a

broad spectrum, and low toxicity ideal for empiric therapy and combination therapy options.

Risk factors

• Patients in the intensive care unit (ICU) and those who are immunocompromised are most at Risk

• factors for nosocomial candidemia :

Hickman catheters (adjusted odds ratio OR 9.5).

gastric acid suppressants (adjusted OR 6.4).

ICU admission (adjusted OR 6.4).

nasogastric tube (adjusted OR 3.7).

administration of antibiotics (adjusted OR 1.5 per antibiotic given).

PATHOGENESIS

Three major routes to the bloodstream:

• Through the gastrointestinal tract mucosal barrier ( the most common mechanism)

• Via an intravascular catheter

• From a localized focus of infection, such as pyelonephritis

Colonization

• It’s an independent predictor of candidemia.

• Although colonization alone does not predict which patients will develop fungemia, candidemia is very uncommon in a patient who is free of colonizing yeasts.

Candida glabrataCandida albicans

Mucosal Candidiasis

Candida Endophthalmitis

Disseminated Candida Skin Lesionin Neuotropenic Patient

Hepatic Lesions Of Candida in Contrast Enhanced CT

QuestionA serum beta glucan test would be expected to be negative for which of the following

• a) Candida albicans

• b) Candida glabrata

• c) Aspergillus niger

• d) Mucor

• e) Histoplasma capsulatum

Diagnosis of Candidemia

• Blood cultureRoutine cultures in 24-72 hours , 50% sensitivity.

• Serology and Bronchoalveolar Lavage.Beta glucan: sensitive(70-85%) but not specific for allfungi EXCEPT MUCOR-not specific for

CandidaGalactomannan: ”Aspergillus Test”

• positive for molds, not yeast and NOT Mucor• Physical exam• Imaging

Significance of Candida

• Blood :

50% sensitivity

Always merits treatment

Catheters should always be replaced.

• Respiratory:

“Never” merits treatment.

• Urine:

Usually insignificant.

• Sterile fluids or tissue:

Obviously needs therapy.

Therapy of Invasive Candidiasisin the ICU

• A definitive diagnosis of IC may be delayed when the clinical and laboratory tools readily available to clinicians are used to assess patients for Candida infection.

• A delay in diagnosis will unfortunately result in a delay in initiation of antifungal therapy, which is associated with increased mortality*.

• Therefore, in the patient with suspected Candidainfection, treatment may need to be initiated on the basis of individual patient factors before a definitive diagnosis is made.

*Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9): 3640-5.*Garey K et al. 2006. Clin Infect Dis. 43: 25-31.

Can we wait for the blood culture results in candidemia?

• Retrospective cohort analysis 1/2001-12/2004: N=157 patients with candidemia.

• Delay in empiric Rx of candidemia till after blood cultures turn positive resulted in higher mortality.

• Start of anti-fungal Rx >12 hrs of drawing a blood culture that turns positive had AOR= 2.09 for mortality, p=0.018.

Morrel M et al. 2005. Antimicrob Agents Chemother. 49(9):3640-5

Candida prophylaxis in the Surgical ICU(patients with high risk for candidemia)

• Eggiman et al. 1999. CCM 27: 1066-1072.– Fluconazole reduced Candida peritonitis and colonization in 43 patients

with complicated GI surgeries. High risk patients.

• Pelz et al. 2001. Ann Surg. 233: 542-548.– Fluconazole reduced candida infection in critically ill surgical patients in

SICU > 3 days. No mortality benefit.

– Predictors included: APACHE II score, fungal colonization, TPN, days to first dose of prophylactic drug.

• Paphitou et al. 2005. Med Mycol. 43(3):235-43.– 327 patients in SICU > 3 days were reviewed to identify predictive factors.

– Combination of DM, HD, TPN, broad-spectrum antibiotics had an invasive candidiasis rate of 16.6% versus a 5.1% rate for patients lacking these characteristics (P = 0.001).

Candida Prophylaxis in MICU & SICU (MV > 48h & expected LOS > 72h)

Garbino et al. Intensive Care

Med. 2002;28:1708-17

Incidence of IC=16%

Incidence of IC=5.8%

Summary (Candida Prophylaxis)

• Prophylaxis is effective in the highest risk patients.

• Prophylaxis reduces the incidence of IC. • A positive impact on mortality has not been

shown except in severely immunocompromised hosts (neutropenia, BMT, or solid organ transplantation).

• Distinction between prophylactic & preemptive therapy needed specially in ICU. Risk ? Dose?.

Azoles

• Floconazole

• approved (FDA) in 1990.

• The azoles work primarily by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase.

• Some laboratories only screen C. glabrata isolates for susceptibility to fluconazole because this species has varying susceptibility.

Azoles

• Voriconazole superior to Floconazole

• However, cross-resistance between fluconazole and voriconazole is seen frequently, especially with C. glabrata.

• Voriconazole has significantly greater in vitro activity against C. krusei isolates compared with fluconazole,

Azoles

• Posaconazole only as an oral.

• It is approved for use as a prophylactic agent for fungal infections – in allogeneic hematopoietic cell transplant

recipients with graft-versus-host disease

– in patients with prolonged neutropenia due to chemotherapy for hematologic malignancies.

– for oropharyngeal candidiasis

– not for systemic candidiasis.

Azoles

• Itraconazol:

• is sometimes used for mucosal candidiasis, but is not used for systemic infections

Azoles

Pfaller: • 610 isolates of C. glabrata : Sensitivity (MIC ≤ 1 µg/ml)

– Posaconazole : 85. 4% – Ravuconazole : 90. 7% – Voriconazole : 92.8%

• 46 fluconazole – resistant isolates of C. glabrata– Posaconazole : 4% – Ravuconazole : 8.7% – Voriconazole : 13%

• Voriconazole Rx : potential for the emergence of voricanazole-resistant Candida glabrata

Echinocandins

• Caspofongin, Anidulafungin, and Micafungin

• It’s noncompetitive inhibitors of the synthesis of 1,3-beta-D-glucan, which is an integral component of the fungal cell.

• Excellent activity against most Candida species.

• Favorable toxicity profiles.

Echinocandins

• Approved for the treatment of candidemia and other forms of invasive candidiasis.

• Preferred over azoles for the initial treatment of candidemia if C. glabrata or C. krusei is identified or suspected.

• Adverse effects are generally mild and include– fever

– thrombophlebitis

– Headache

– elevated aminotransferases.

Amphotericin B

• A polyene antifungal agent that disrupts fungal cell wall synthesis because of its ability to bind to sterols, primarily ergosterol, which leads to the formation of pores that allow leakage of cellular components.

• Amphotericin B deoxycholate, which was the standard drug for decades, demonstrates rapidly cidal in vitro activity against most species of Candida.

Amphotericin B

• It is also associated with significant nephrotoxicity. • This has led to the development of various lipid-

based derivatives, including • Liposomal Amphotericin B• Amphotericin B lipid complex (ABLC). • Amphotericin B colloidal dispersion (ABCD) is

used infrequently, in part because it causes more infusion-related reactions than Amphotericin B deoxycholate.

• These lipid-based compounds have much less toxicity than Amphotericin deoxycholate but are significantly more expensive.

Factors to be considered

• History of recent azole exposure• Prevalence of different Candida species and current

antifungal susceptibility data in the clinical unit and medical center

• Severity of illness• Relevant comorbidities that increase the risk

of Floconazole -resistant Candida species (e.g., neutropenia )

• Evidence of involvement of the central nervous system, cardiac valves, eyes, and/or visceral organs

• History of intolerance of to an antifungal agent

RECOMMENDATIOSfor treatment of candidemia

• Non-neutropenic patients :

If clinically stable, who have not been exposed to recent azole therapy, and who are in clinical units or medical centers in which C. glabrata or C. krusei are uncommonly isolated (<15 percent of all species causing candidemia), the initial therapy with Fluconazole rather than an Echinocandins.

RECOMMENDATIONSfor treatment of candidemia

• In non- neutropenic patients with moderately severe or severe infections and/or who are at increased risk of C. glabrata or C. krusei infection, we favor an Echinocandins and we not use Floconazole as initial therapy, prior to the identification of the causative species.

• However, in patients who have documented C. glabrata infection, who are already improving clinically on fluconazole or Voriconazole, and whose follow-up blood cultures are negative, continuing with the azole is reasonable.

Aspergillosis

• The term "aspergillosis" refers to illness due to allergy, airway or lung invasion, cutaneousinfection, or extrapulmonary dissemination caused by species of Aspergillus, most commonly A. fumigatus, A. flavus, and A. terreus

RISK FACTORS

Underlying conditions that compromise pulmonary and systemic immune responses to inhaled Aspergillus.

Classic risk factors include:• Severe and prolonged neutropenia • Receipt of high doses of glucocorticoids• Chronic impaired cellular immune responses

– Immunosuppressives administered to treat autoimmune diseases and to prevent organ rejection, and AIDS

CLINICAL FEATURES

Invasive aspergillosis most frequently occurs in the lungs or sinuses after inhalation of conidia, although, less commonly, disease can spread from the gastrointestinal tract, or result from direct inoculation into the skin.

CLINICAL FEATURESPULMONARY

• Fever, chest pain, shortness of breath, cough, and/or hemoptysis.

• The classic triad that has been described in neutropenic patients with pulmonary aspergillosis is

– fever

– pleuritic chest pain

– hemoptysis

CLINICAL FEATURESPULMONARY

• Chest x-ray is insensitive for detecting the earliest stages

• CT scans abnormality is variable, depending upon the host and the type of disease: – bronchopneumonia

– angioinvasive aspergillosis,

– Tracheobronchitis

– chronic necrotizing aspergillosis.

- small nodules (<1 cm) were most common (43 %).

- consolidation (26 %).

- large nodules (masses, 21 %).

- peribronchial infiltrates (9 %).

CLINICAL FEATURESPULMONARY

In neutropenic patients, in whom the initial findings typically include nodules that have surrounding ground glass infiltrates (halo sign), reflecting hemorrhage into the area surrounding the fungus.These nodules typically enlarge, even during appropriate therapy, and may eventually cavitate, producing the air-crescent sign

CLINICAL FEATURESTracheobronchitis

• Most often described in lung transplant recipients and patients with AIDS.

• Affected patients typically present with prominent dyspnea, cough, and wheezing; they occasionally expectorate intraluminal mucus plugs.

• Chest imaging may be normal or reveal areas of airway thickening, patchy infiltrates, consolidation, or centrilobular nodules.

CLINICAL FEATURESDisseminated infection

• Disseminated infection — In the presence of angioinvasive disease, Aspergillus spp can disseminate beyond the respiratory tract to multiple different organs, including the skin, brain, eyes, liver, and kidneys.

• Disseminated infection is associated with a very poor prognosis.

CLINICAL FEATURESRhinosinusitis

• In the paranasal sinuses, aspergillosis can present in an identical fashion to mucormycosis. However, rhinocerebral aspergillosis is usually seen in neutropenic patients, whereas mucormycosis more often occurs in those with diabetes mellitus.

• nasal congestion, fever, and pain in the face and around the eye are common presenting features.

• If the orbit becomes involved, additional symptoms may include blurred vision, proptosis, and chemosis. The infection can also extend locally into the vasculature and the brain, leading to cavernous sinus thrombosis and a variety of central nervous system (CNS) manifestations.

CLINICAL FEATURESRhinosinusitis

• Imaging findings may be subtle and can include focal soft tissue lesions, subtle focal bony erosions, focal enhancement of the sinus lining on magnetic resonance imaging or focal hypodense areas on computed tomography scan .

• Biopsy is necessary to establish the diagnosis; multiple biopsies are sometimes necessary

CLINICAL FEATURESChronic necrotizing

chronic cavitatry pulmonary aspergillosis

• Patients who have underlying chronic lung disease are at risk for indolent forms of pulmonary aspergillosis, characterized by cavities or infiltrates.

• Presumably, the slowly progressive nature of this infection is a function of the host immune response, which is enough to hold the organism in check, but not to eliminate it.

CLINICAL FEATURESChronic necrotizing and chronic

cavitarty pulmonary aspergillosis

• Cough, weight loss, fatigue, and chest pain are common, and the chest x-ray shows a slowly progressive lesion, which can be better defined by CT scanning. However, interpretation of radiologic studies may be complicated by the presence of concomitant lung disease, since this is the setting in which chronic invasive aspergillosis usually occurs.

CLINICAL FEATURES

Central nervous system

• (CNS) aspergillosis may occur in the setting of disseminated infection, as well as from local extension from the paranasal sinuses. Patients with CNS involvement with Aspergillus spp may present with seizures or focal neurological signs.

• * very poor prognosis.

CLINICAL FEATURES

Central nervous system • In a study of the computed tomography

and/or magnetic resonance imaging findings associated with CNS aspergillosis, three patterns were observed :

• A- Ring-enhancing lesions consistent with brain abscesses .

• B- Cerebral cortical and subcortical infarction, with or without superimposed hematomas .

• C- Mucosal thickening of a paranasal sinus with secondary intracranial duralenhancement consistent with direct extension from the sinuses .

CLINICAL FEATURESEndophthalmitis

• Involvement of the deep structures of the eye results not only from hematogenous spread. In other patients, corneal infection or direct inoculation following trauma is the genesis of infection . Patients present with eye pain and visual changes .

• Progressive infection is characterized by destruction of multiple components of the eye. The outcome is usually poor with loss of useful vision in the affected eye, and a requirement for enucleation in some cases.

CLINICAL FEATURESEndocarditis

• Aspergillus spp are second only to Candida spp as a cause of fungal endocarditis .

• This infection occurs primarily in patients with prosthetic heart valves. In many patients, infection occurs at the time of surgery, with the fungus contaminating the surgical site. Patients may present at any time postoperatively.

• Other patients at risk for the development of Aspergillus endocarditis include patients with indwelling central venous catheters and intravenous drug users.

CLINICAL FEATURESEndocarditis

• Patients typically present with fever and embolic phenomena. Blood cultures are rarely positive, even when a fungal isolator system is used. Microscopic examination of an embolus will reveal the typical hyphae suggestive of aspergillosis, but definitive microbiologic diagnosis depends upon culture of the organism.

• The prognosis of Aspergillus endocarditis is poor. Even with combined medical and surgical therapy, the mortality rate has approached 100 percent

CLINICAL FEATURES

Cutaneous Aspergillosis• A healthy hosts can develop cutaneous disease in

surgical wounds. While burn victims, neonates, and solid organ transplant recipients tend to develop primary cutaneous disease in the presence of prolonged local skin injury, patients with hematologic malignancies and hematopoietic cell transplant recipients more frequently develop disease due to contiguous or blood-borne invasion.

• Diagnosis can only be verified by skin biopsy, which should be taken from the center of the lesion and reach the subcutaneous fat.

CLINICAL FEATURESGastrointestinal aspergillosis

• Aspergillosis can involve the (GI) tract, causing focal invasion as a primary site of inoculation and presenting as typhlitis, colonic ulcers, abdominal pain, and/or GI bleeding . Direct inoculation from the GI tract is likely, with risk factors including neutropenia, receipt of glucocorticoids, and mucosal breakdown (mucositis).

Diagnosis of invasive aspergillosis

• It is based upon both isolating the organism (or markers of the organism) and the probability that it is the cause of disease.

• Culture in combination with evidence of tissue invasion on histopathology, or culture from a normally sterile site, provides the most certain evidence of invasive aspergillosis

Diagnosis of invasive aspergillosis

• Direct examination of respiratory specimens:

• Gomori methenamine silver can be used to stain cytology preparations. Organisms can be observed as narrow (3 to 6 microns wide), septated hyaline hyphae with acute angle (45°) branching .

• However, several filamentous fungi, including Scedosporium spp and Fusarium spp, have similar appearances to Aspergillus spp on direct microscopy.

Diagnosis of invasive aspergillosis

• CULTURE:

• Often visible in culture within one to three days of incubation.

• In multicenter surveillance studies only 25 to 50 percent of hematopoietic cell transplant recipients who met criteria for invasive aspergillosis based upon galactomannan antigen results had positive cultures

Diagnosis of invasive aspergillosis

• Galactomannan antigen detection:• galactomannan antigen can be detected in the

serum before the presence of clinical signs or symptoms

• False positive serum results have been demonstrated in patients who are receiving certain beta-lactam antibiotics, especially PIP/TAZO.

• False positive results may be seen with infections caused by organisms that share cross-reacting antigens, (eg, Fusarium species , Histoplasma capsulatum ).

Diagnosis of invasive aspergillosis

• Galactomannan antigen detection

• A meta-analysis that included 27 studies with a total of 4000 patients (mainly with hematologic malignancies), reported that overall sensitivity and specificity of the galactomannan antigen assay for proven invasive aspergillosis were 71 percent (95% CI 68-74 percent) and 89 percent (95% CI 88-90 percent), respectively

Diagnosis of invasive aspergillosis

• Bronchoalveolar lavage fluid:• A retrospective study was performed in which

251 patients who were at risk for invasive aspergillosis and who presented with unexplained nodular lesions or consolidation on lung imaging underwent galactomannan antigen testing of BAL fluid [8].

• the sensitivity of galactomannan antigen testing of BAL fluid for diagnosing proven or probable invasive aspergillosis was 86 percent and the specificity was 91 percent.

Diagnosis of invasive aspergillosis

• Beta-D- glucan assay:

• In a 2011 meta-analysis that included 16 studies evaluating beta-D- glucan assays for the diagnosis of invasive fungal infections, the pooled sensitivity was 77 % ,and the pooled specificity was 85%

Diagnosis of invasive aspergillosis

• Polymerase chain reaction:

• A meta-analysis suggested that sensitivity and specificity of PCR to detect invasive aspergillosis was 88 and 75%

Diagnosis of invasive aspergillosis

• Imaging

• We have discussed before.

Treatment of invasive aspergillosis

• Voriconazole rather than a formulation of Ampho B (Grade 1, B).

• Echinocandins such as Caspo may also be effective therapy, but have not been adequately studied.

• Surgical debridement is usually required for the treatment of Aspergillus rhinosinusitis,

Mucormycosis

• Mucormycosis is manifested by a variety of syndromes in humans, particularly in immunocompromised patients and those with diabetes mellitus. Devastating rhino-orbital-cerebral and pulmonary infections are the major syndromes caused by these fungi

Mucormycosis

• A review of 929 cases of mucormycosis that were reported between 1940 and 2003 noted that diabetes was the most common risk factor, found in 36 percent of cases, followed by hematologic malignancies (17%), and solid organ or hematopoietic cell transplantation (12 %).

Mucormycosis

• PATHOGENESIS :

• Rhizopus organisms have an enzyme, ketone reductase, which allows them to thrive in high glucose, acidic conditions.

Mucormycosis

• Mucormycosis is characterized by infarction and necrosis of host tissues that results from invasion of the vasculature by hyphae. The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, which is presumed to start with inhalation of spores into the paranasal sinuses of a susceptible host.

Mucormycosis

• Pulmonary mucormycosis is a rapidly progressive infection that occurs after inhalation of spores into the bronchioles and alveoli. Pneumonia with infarction and necrosis results, and the infection can spread to contiguous structures such as the mediastinum and heart or disseminate hematogenously to other organs.

Mucormycosis

• DIAGNOSIS:

• Histopathology with culture confirmation. However, culture often yields no growth, and histopathologic identification of an organism with a structure typical of Mucorales may provide the only evidence of infection.

• PCR-based technique used in this study appears promising.

Mucormycosis

• TREATMENT:

• Ampho B (lipid formulation) is the drug of choice. Oral Posaconazole is used as step-down therapy for patients who have responded to Amphotericin B and rarely as salvage therapy for patients who don't respond to or cannot tolerate Amphotericin B

THANK YOU

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• 8- D'Haese J, Theunissen K, Vermeulen E, et al. Detection of galactomannan in bronchoalveolar lavage fluid samples of patients at risk for invasive pulmonary aspergillosis: analytical and clinical validity. J ClinMicrobiol 2012; 50:1258.

REFERENCES

• 9- Karageorgopoulos DE, Vouloumanou EK, Ntziora F, et al. β-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 2011; 52:750.

• 10- Mengoli C, Cruciani M, Barnes RA, et al. Use of PCR for diagnosis of invasive aspergillosis: systematic review and meta-analysis. Lancet Infect Dis 2009; 9:89.