INTRODUCTION

Fungal infections occur not only in immunocompromised

patients (see chapter on The Immunocompromised Patient),
but also in patients who are under critical care for various
problems, e.g. acute infections, trauma or major surgery, and
who have a normal immune defense mechanism to start with.
Perhaps the most important cause of fungal overgrowth and
any systemic or deep-seated fungal infection in these patients
is the prolonged use of broad-spectrum antibiotics which
alter the bacterial flora, and promote the growth of unusual
resistant organisms and fungi. Acute or critical illnesses in
the course of time also temporarily depress the immune
mechanisms within the body to some extent. Thus patients
with unresolved or persistent septic infections, or long-
standing untreated foci of infection, e.g. undrained abscesses,
show a decreased capacity to respond to immunological
challenges. All major surgical procedures are also followed
by a depressed immunological response; this is related to
an increase in suppressor cells, a fall in T4 lymphocytes, and
alterations in lymphokine production. These changes are
however temporary, and are quickly reversed as recovery
progresses. In the presence of complications, the postoperative
changes noted above are protracted, and may well play a
role in predisposing the patient to both bacterial and fungal
infections. Finally, poor nutritional status further depresses
the immune defense mechanisms. Thus a combination of
various factors, varying in degree in each individual critically
ill patient, form a background against which fungal infections
can occasionally supervene. The environment too perhaps
has some part to play, e.g. clear-cut nosocomial outbreaks
of invasive aspergillosis have been described in critical care
units, and these have been related to the marked increase in
air-borne spores of Aspergillus fumigatus in these units.
The important invasive fungal infections encountered
in a critical care setting are candidiasis and aspergillus
infections. Occasionally, infections with the mucor species
are observed, particularly in diabetics or other severely
immunocompromised patients. Other fungal infections are
being increasingly recognized in the West; in our country,
however, we are as yet blissfully unaware of their possible
occurrence.
CANDIDAL BLOODSTREAM INFECTIONS
Epidemiology
Candida represents the commonest form of invasive fungal
disease
1
in most ICUs all over the world. It now accounts for
12% of all hospital-acquired bloodstream infections (BSIs).
Though there was a major increase in candida BSI in the 1980s,
the incidence of BSI has now stabilized or even declined in
the West. The incidence of BSI with candida varies in different
ICUs in our country. We have noted a definite increase in
candidal BSI in our unit; perhaps this holds for many units in
the large urban centers of India. An important epidemiological
trend in many western centers is the shift in the distribution
of candidal species responsible for BSI, Candida albicans
being responsible for only half of all BSIs caused by yeast.
Recent data from the Prospective Antifungal Therapy Alliance
(PATH) database from 2004 to 2008 showed that the incidence
of candidemia caused by the non-albicans candida species
was higher (54.4%) than C. albicans (45.6%). The commonest
non-albicans species that were isolated being C. glabrata,
C. parapsilosis, C. tropicalis, C. krusei.
2
In our unit C. albicans
is no longer the main isolate BSI; there is a slow but definite
increase in isolates of C. tropicalis, C. glabrata, C. parapsilosis,
C. krusei and also an occasional presence of other rare candida
species. C. tropicalis now is the main bloodstream isolate
Invasive Fungal Infections in the ICU
C H A P T E R
47
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561 Chapter 47 Invasive Fungal Infections in the ICU
constituting 14% of all bloodstream yeast isolates. It is possible
that the increasing incidence of non C. albicans species may
be related to the extensive use of fluconazole not only as
treatment but also as a prophylactic drug in patients in whom
fungal infections are likely to occur. This epidemiological
shift is obvious in the West but slowly making itself felt in
our country as well has important implications for therapy,
because of intrinsic resistance of C. glabrata and C. krusei
to fluconazole. Figure 1 illustrates the distribution of yeasts
isolated from blood cultures and resistance to fluconazole.
A study on bloodstream fungal infection from the Sir
Ganga Ram Hospital, New Delhi, India,
3
has also shown a
significant increase in both candidemia and total antifungal
use. There was increase in infections due to the non-
albicans species and this was correlated to increasing use
of fluconazole. The study also revealed the emergence and
isolation of a novel species C. haemolunii with decreased
susceptibility to both amphotericin B and azoles. The authors
of this study have commented that decreased susceptibility
to fluconazole, as well as the threat of emergence of cross-
resistance to voriconazole against the background of high
azole consumption, may limit the use of these agents as
presumptive therapy for candida BSIs.
A study by Chakrabarti A et al (presented as a poster at the
ID Week San Diego, 2012) included 25 ICUs across India and
found that the incidence of candidemia was 7.0/1,000 ICU
admissions over a 6-month period. This study highlighted the
distribution of candidia species in these patients, the most
common being C. tropicalis and the emergence of uncommon
species like C. haemulonii and C. rugosa, C. guilliermondii,
C. pelliculosa and also of azole resistant C. albicans and C.
tropicalis. Figure 2 shows the distribution of various candida
species in this study.
Fig. 1: Fluconazole resistance among yeast isolated from blood cultures
(20102012)
Fig 2 : Distribution of various candida species in candidemia patients
Source: Candidemia in Intensive Care Units of India: a Six Months Interim Report on Active Surveillance. ID week 2012, San Diego. Poster Abstract Session: Clinical
Mycology and Fungal Virulence October 18, 2012.
13
562 Section 13 Fever and Acute Infections in a Critical Care Setting
Risk Factors for Invasive Candidiasis
Specific to the ICU, several risk stratification schemes exist to
identify patients at high risk for candidemia. A multicenter
cohort study from Spain
4
involving 1,699 adult ICU patients
identified surgery, multifocal colonization, TPN and
severe sepsis to be a strong predictor of candidal infection.
Another large cohort study from American and Brazilian
ICUs identified the following features to predict invasive
candidiasis. These factors were antibiotics, central venous
catheter (CVC), TPN, dialysis, major surgery, pancreatitis, use
of steroids and other immunosuppressive agents.
5
Both these studies in our opinion have omitted one major
risk factor for invasive candidiasisduration of ICU stay.
The longer the stay in the ICU, the greater the chance of the
patient developing a fungal infection. What combination of
risk factors stated above are more likely to cause invasive
candidiasis is undetermined. The risk factors for invasive
candidiasis are listed in Box 1.
According to the Indian study by Chakrabarti et al.
quoted earlier, central venous catheterization, urethral
catheterization and mechanical ventilation were seen as
significant risk factors associated with candidemia in the ICU.
Box 2 shows the various risk factors linked with candidemia
as found in this study.
Proof of invasive candidiasis rests in a positive blood
culture for candida. Unfortunately blood cultures are positive
only in 5070% of patients with invasive candidiasis. It is
important to note that a positive blood culture for candida
should never be ignored as a possible contaminant and
should prompt search for the source of infection. Biopsy of
a specific lesions from a normally sterile site (e.g. lung, liver)
demonstrating the histopathology of invasive candidiasis
can give a definite diagnosis, but this is often not feasible in
critically ill patients. Because of these difficulties in diagnosis,
a non-culture based diagnosis test has been researched upon
and recently approved by the Food and Drug Administration.
This test is the 1-3-b-D-glucan test. 1-3-b-D-glucan is an
important major component of the fungal cell wall and it
can be detected from the blood and assayed in patients with
invasive candidiasis. It has a sensitivity of 75100% and a
specificity of 88100%. However, this is a broad spectrum assay
that detects not just candida but also Aspergillus, Fusarium,
Acremonium, Saccharomyces species.
6
The test therefore
requires careful interpretation. In fact none of the currently
available tests allow of a reliable diagnosis. Hence, in a febrile
critically ill patient who is unresponsive to antibiotics and who
has risk factors for invasive candidiasis, empiric treatment
against candidal infection is justified.
Clinical Features
Pyrexia of unknown origin not responding to antibiotics
therapy is the key presentation in most cases. Candidal
infection can involve any organ system in invasive candidiasis.
Liver and spleen involvement lead to hepatosplenomegaly. The
kidney, lungs, brain may also be involved. Endophthalmitis is
a rare but noteworthy feature in some patients.
Treatment
7
Treatment should not await a confirmed culture. High risk
cases presenting with fever and showing a sharp clinical
deterioration should be promptly started on antifungal
therapy. The CVC should as far as possible be removed. If
absolutely necessary a new central line on the opposite side
should be inserted.
For non-neutropenic hemodynamically stable patients,
fluconazole is the drug of choice unless there is a suspicion of
a fluconazole resistant speciese.g. history of a recent azole
exposure or a history of previous colonization by C. glabrata,
C. krusei. If used empirically the drug is given IV in a dose of
800 mg/day, the dose being adjusted with reference to renal
function. The drug is continued till the offending candida
species has been identified.
In neutropenic patients, or in hemodynamically unstable
patients, or in ICUs where there is significant infection rate
with fluconazole resistant species, an echinocandin is the drug
of choice till species identification of the fungal isolate is made.
The echinocandin generally used is caspofungin. Two other
commercially available echinocandins are also available.
These are micafungin and anidulafungin. Experience with
Box 1: The risk factors for invasive candidiasis
x Prolonged use of antibiotics
x Corticosteroids, immunosuppressive therapy
x Central venous catheterization
x Prolonged ICU stay
x Surgery
x TPN
x Diabetes, malignancy
x Organ transplant
x Dialysis
x Pancreatitis
x Multifocal colonization
Box 2: Risk factors associated with candidemia in the ICU
Risk factors No. of cases
x CVL catheterization 218
x Urethral catheterization 201
x Invasive mechanical ventilation 169
x Drainage catheter 88
x Antibiotic therapy 63
x Dialysis 55
x Total parenteral nutrition 55
x Steroid therapy 61
Source: Candidemia in Intensive Care Units of India: a Six Months Interim Report
on Active Surveillance. ID week 2012, San Diego. Poster Abstract Session:
Clinical Mycology and Fungal Virulence October 18, 2012.
13
563 Chapter 47 Invasive Fungal Infections in the ICU
the last two echinocandins is however limited. Lyophylized
amphotericin can also be used if there is intolerance to
or unavailability of an echinocandins. Voriconazole is
an acceptable alternative but offers no advantage over
fluconazole. It is to be recommended as step-drown oral
therapy for selected cases of candidiasis due to C. krusei or
voriconazole susceptible C. glabrata. If infection has been
caused by C. parapsilosis, fluconazole is preferred as these
fungi are less susceptible to echinocandins.
The duration of therapy recommended is 14 days from the
last positive cultures. If cultures remain negative treatment
should continue for 710 days after the patient is afebrile.
Treatment may at times needs to be longer depending on the
degree and site involved.
INVASIVE ASPERGILLOSIS
Invasive aspergillosis is less commonly encountered than
invasive candidiasis. Sinopulmonary infection is most often
observed, though many organ systems can be involved. A.
fumigatus, A. flavus and A. niger account for nearly all human
disease. Though the disease may rarely be encountered in
immunocompetent individuals, it is most frequently seen in
immunocompromised or immunosuppressant patients in
the ICU.
The risk factors are
T Prolonged neutropenia.
T Corticosteroids and immunosuppressive therapy.
T Solid organ transplant patients.
T Hemopoietic stem cell transplant patients.
T Advanced HIV with CD counts often below 100/cm.
T Chronic granulomatous disease.
The clinical features have been discussed in the chapter
on The Immunocompromised patient.
Demonstration of the aspergillus in biopsy samples is the
gold standard for diagnosis. A positive aspergillus culture
from the blood though uncommon is also confirmatory. A
bronchoalveolar lavage (BAL) culture positive for aspergillus
should lend strong suspicion for invasive pulmonary
aspergillosis, if clinical features are compatible with the
diagnosis.
Computed tomography (CT) findings of the chest may
suggest the diagnosiscavitations, nodules, wedge shaped
pleural based shadows suggesting pulmonary infarcts, the
halo sign, the crescent sign may be observed. The clinical
and imaging features as also the value of the galactomannan
test and the b glucan test have been commented upon in the
chapter on The Immunocompromised Patient.
Treatment
8
According to a multicenter randomized open label trial
comparing amphotericin B to voriconazole as initial therapy
for invasive aspergillosis, voriconazole was associated with
increased survival (76% vs 58%). Voriconazole is therefore
generally recommended as first line therapy. Before
voriconazole, itraconazole was used intravenously against
invasive aspergillosis with reasonable success. Voriconazole
has now replaced itraconazole in treatment. Posaconazole is
an additional extended triazole for treating refractory disease.
The echinocandins (caspofungin) can be used as
alternative therapy to voriconazole particularly in patients
who cannot tolerate voriconazole or who are refractory
to standard therapy. Many units use a combination of
amphotericin B or amphotericin B lipid formulation and
voriconazole in the treatment of severe invasive aspergillosis.
There is however very little evidence for the increased efficacy
and safety of this combination therapy.
The final drugs recommended as salvage therapy for
invasive aspergillosis are micafungin and anidulafungin,
two new echinocandins.
8
The experience with micafungin or
anidulafungin is limited. The drugs are best kept in reserve
for salvage therapy.
MUCORMYCOSIS
Mucormycosis is a life threatening mold infection caused
by fungi belonging to the older Mucorales. The organisms
causing this mold infection include Rhizopus, Rhizomucor,
Absidia and Mucor. These organisms almost always have a
predilection for immunocompromised patients and present
with a rapid onset angioinvasive disease. Risk factors include
diabetes, acidosis, solid organ and bone marrow transplant
recipients, use of immunosuppressant drugs, iron overload,
deferoxamine treatment.
Diabetes and in particular diabetic acidosis are major
risk factors. Patients present with rhinocerebral disease that
causes destruction of the nasal septum and paranasal sinuses;
the disease then extends into and destroys the orbit and
penetrates upward into the brain.
Pulmonary mucormycosis is the typical presentation in
post-transplant patients. Invasion of vessels with ischemic
necrosis of the tissue is a typical feature of this fungal disease.
Treatment
9
is with high dose amphotericin B 11.5 mg/kg
per day or amphotericin B lipid preparation in doses of 57.5
mg/kg per day. Azoles and echinocandins are ineffective in
mucormycosis.
Urgent surgical treatment is always necessary to excise and
debride involved tissue in rhinocerebral disease. Surgery may
also be necessary in pulmonary mucormycosis.
Early diagnosis is critical for survival. Diagnosis is made on
clinical grounds and the presence of the fungus in scrapings
of involved tissue, and of the fungus in the discharge from
infected tissue. Delay in initiating treatment increases
mortality. Posaconazole has been recently used as prophylaxis
in severely immunocompromised patients. This drug has also
occasionally been used as salvage therapy but is not a standard
treatment for the disease.
The efficacies of antifungal agents are listed in Table 1.
Doses and dosing adjustment of commonly used antifungal
agents are listed in Table 2.
13
564 Section 13 Fever and Acute Infections in a Critical Care Setting
Table 2: Doses of commonly used antifungal agents
Drug Dose Dose adjustment
Invasive Candidiasis
Amphotericin B 0.61 mg/kg/day, IV None, careful monitoring of renal
and liver function
Amphotericin B lipid formulation 35 mg/kg/day, IV None, careful monitoring of renal
and liver function
Fluconazole 400800 mg/day, IV or PO Renal insufficiency
Voriconazole IV, 6 mg/kg every 12 hr for 2 doses followed by 34 mg/kg
every 12 hr
PO, <40 kg 100 mg every 12 hr; >40 kg 200 mg every 12 hr
Hepatic dysfunction
Echinocandins
Caspofungin 70 mg loading dose followed by 50 mg/day, IV Hepatic dysfunction
Micafungin 100 mg/kg
Anidulafungin 200 mg loading dose followed by 100 mg/day, IV None
Invasive Aspergillus
Amphotericin B 11.5 mg/kg/day, IV As listed above
Amphotericin B lipid formulation 5 mg/kg/day, IV As listed above
Voriconazole As listed above As listed above
Echinocandins As listed above As listed above
Itraconazole IV, 200 mg every 12 hr for 4 doses followed by 200 mg/day
PO, 200400 mg/day
Multiple drug interaction, IV not
recommended for CrCl <30 mL/min
Mucormycosis
Amphotericin B 11.5 mg/kg/day, IV As listed above
Amphotericin B lipid formulation 5 mg/kg/day, IV As listed above
Table 1: Efficacy of antifungal agents in fungal infections
Amphotericin B or Amphotericin
B lipid formulation
Fluconazole Voriconazole Echinocandin
C. Albicans + + + +
C. Tropicales + + + +
C. Glabrata + - - +
C. Krusei + - + +
C. Parapsilosis + + + +/-
Aspergillus + - + +
Cryptococcus + + + -
Mucorales + - - -
Fusarium - - + +/-
Note: Aspergillus terreus is intrinsically resistant to amphotericin B. Aspergillus lentulus is intrinsically resistant to azoles.
This is followed by a brief description on the role of
amphotericin B in fungal infections.
Amphotericin B
For poor developing countries, the cheapest of all antifungal
agents against invasive fungal infection is amphotericin B
deoxycholate and it is therefore appropriate to add a few
additional remarks on this drug. The drug has important side
effects and in critically ill patients it is best to start with a test
dose of 1 mg in adults (0.5 mg in children <30 kg) given over
1 hour. This is followed after 4 hours by a dose of 0.5 mg/kg
administered over 34 hours. Even if the test dose produces
Abbreviations: PO, by mouth; IV, intravenous; CrCl, creatinine clearance.
13
565 Chapter 47 Invasive Fungal Infections in the ICU
a reaction, 10 mg is administered after 4 hours. The dose is
increased by 1520 mg daily so that the dose of 0.51 mg/
kg is reached within 37 days. The drug is then continued
daily till a total dose of at least 11.5 g is administered. In
granulocytopenic patients empirically given amphotericin
B should be continued till recovery from granulocytopenia
ensues. Deep visceral infections may require a total dose of
23 g or even more.
Amphotericin B should be given in a 5% dextrose solution.
Electrolyte solutions should be avoided, as they cause
precipitation of the amphotericin B suspension. Side effects
are common; pyrexia with chills is the most frequent side
effect observed. Intravenous hydrocortisone in a dose of 50 mg
given at the time of infusion often controls a severe pyrexial
reaction. Other important side effects include hypotension,
nausea, thrombophlebitis, hypokalemia and renal dysfunction
with a rise in the serum creatinine level. A significant rise
in the latter warrants a temporary stoppage of the drug; it
is restarted when the creatinine level drops. Permanent
renal tubular damage may occur when large doses (34 g) of
amphotericin B are used.
Amphotericin B does not achieve significant concentration
in the urine, CSF or peritoneal fluid. In cases of fungal
meningitis, intrathecal administration of amphotericin B
may be combined with intravenous therapy. The intrathecal
dose is 0.51 mg dissolved in the CSF. The total dose should
not exceed 15 mg. Arachnoiditis and motor or sensory
disturbances may occur as complications. An Omaha reservoir
is sometimes used for instillation of amphotericin B into the
cerebral ventricles in patients with CNS fungal infection. The
danger of introducing secondary bacterial infection is ever
present with this mode of administration.
Clinical Resistance to Amphotericin B
Clinical resistance to amphotericin B is observed in severely
immunocompromised patients, in patients with infected
prosthetic valves or other foreign bodies, and in advanced
visceral fungal infections involving the liver, spleen or kidneys.
Hepatosplenic candidiasis is a clinically resistant
infection which may prove resistant to even high doses of
amphotericin B. The development of fever, abdominal pain,
or liver cell dysfunction occurring in a patient recovering
from granulocytopenia should raise suspicion of candidal
infection within the abdomen. Investigations should
include ultrasound, CT and, if necessary, MRI imaging of
the abdominal organs. A combination of amphotericin B
and flucytosine or fluconazole should be promptly started.
Therapy may need to be continued for several months, and
may yet be unsuccessful.
Microbiological resistance to amphotericin B has
been reported in C. albicans, C. tropicales, other candida
species, as also against other fungiTrichosporon beigeli,
Fusarium species, and Pseudallescheria boydii species.
10

In the West, Trichosporon beigelii, Fusarium species, and
P. boydii species are increasingly recognized causes of
systemic fungal infections.
10
A combination therapy of high
doses of amphotericin B with flucytosine or fluconazole
is recommended as initial treatment. If unsuccessful,
fluconazole plus flucytosine is advised for systemic fungal
infections due to polyene resistant fungi.
10
Systemic fungal infections originating from an infected
foreign body, viz. an infected prosthetic valve, can never be
controlled unless the foreign body is first removed. Fungal
valvular endocarditis invariably necessitates removal of the
valve. Further examples where removal of infected foreign
bodies is mandatory include
T Removal of central venous lines.
T Removal of infected ventriculoperitoneal shunts in pati-
ents with fungal infections of the CNS.
T Removal of urinary catheters in patients with candidiasis
involving the urinary tract.
T Removal of a dialysis catheter in fungal peritonitis
associated with peritoneal dialysis.
It is not enough to use antifungal drugs in the treatment of
systemic fungal infections in critically ill patients. As always,
overall critical care is of vital importance. An assiduous
search to determine why systemic fungal infection occurred,
and whether the source of infection can be controlled or
eradicated is of great importance.
Flucytosine
Flucytosine is an antifungal drug that has not been discussed
earlier. It is effective both orally and on intravenous use and
is active against candida species and cryptcoccus. It enters
cerebrospinal fluid as also urine and peritoneal fluid and
is particularly useful in fungal (especially cryptococcal)
infections involving the meninges and/or the neuroaxis. It
excretion is reduced in renal failure; the daily dose should
therefore be adjusted in these patients. Its main disadvantage
is the development of either primary or secondary drug
resistance to a significant number of fungal isolates. There
is also the danger of bone marrow suppression, particularly
with use of toxic doses. The dose of flucytosine is 100 mg/
kg of bodyweight orally, divided in four equal doses every 6
hours. The dose for intravenous infusions is 50 mg/kg infused
over 2040 minutes every 6 hours. If possible blood levels of
the drug should be estimated and not allowed to go beyond
100120 g/dL.
As has already been mentioned, combination therapy
with amphotericin B and flucytosine is often used in relatively
resistant fungal infection. The drugs when used together
are synergistic, so that the dose of amphotericin may be
reduced in patients who do not tolerate its full dose. In
cryptococcal meningitis, a combination therapy of 0.30.6
mg/kg of amphotericin B and the usual dose of flucytosine
is more effective in sterilizing the CSF and prevents relapse.
Alternatively, IV amphotericin B (0.7 mg/kg per day) can
be used for the first 2 weeks, followed by fluconazole or
flucytosine orally.
13
566 Section 13 Fever and Acute Infections in a Critical Care Setting
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