Antifungal Use for Opportunistic Infection in HIV Patients

13 Pages·2011·0.05 MB·English

Article ID: WMC002674 2046-1690
Antifungal Use for Opportunistic Infection in HIV
Patients: Comparison of Efficacy and Safety
Corresponding Author:
Ms. Sabariah N Harun,
Lecturer , School of Pharmaceutical Sciences, Universiti Sains Malaysia - Malaysia
Submitting Author:
Ms. Mei H E,
Undergraduate student, School of Pharmaceutical Sciences, Universiti Sains Malaysia - Malaysia
Article ID: WMC002674
Article Type: Review articles
Submitted on:18-Dec-2011, 09:21:17 AM GMT Published on: 19-Dec-2011, 03:45:21 PM GMT
Article URL: http://www.webmedcentral.com/article_view/2674
Subject Categories:AIDS
Keywords:HIV, Opportunistic fungal infection, Comparison, Efficacy, Safety
How to cite the article:E M H, Lai K L, Mohd Shariff M S, Mohd Razib N A, Sia Z K, Wang T H, Harun S N.
Antifungal Use for Opportunistic Infection in HIV Patients: Comparison of Efficacy and Safety . WebmedCentral
AIDS 2011;2(12):WMC002674
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original
author and source are credited.
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Antifungal Use for Opportunistic Infection in HIV
Patients: Comparison of Efficacy and Safety
Author(s): E M H, Lai K L, Mohd Shariff M S, Mohd Razib N A, Sia Z K, Wang T H, Harun S N
Abstract adverse reactions or side effects. Therefore, dose
adjustment and therapeutic drug monitoring must be
performed accordingly and routinely to avoid
unnecessary complications.
Background: Fungal infections always occur in HIV
Key words: HIV, opportunistic fungal infection,
patients due to depressed immunity. The most
comparison, efficacy, safety.
common fungal infections are candidiasis,
cryptococcal meningitis and histoplasmosis.
Objectives: To compare the efficacy and safety of the Introduction
antifungal available for the three most common
opportunistic fungal infections in HIV patients.
Methods: The databases that we used to gather the
In Malaysia, the first HIV infection case was reported
information are PubMed, Lancet, Clin Infect Dis,
in the year 1986 (Wang & Ismail, 1999). HIV pandemic
SpringerLink, Ann Intern Med, J Clin Microbiol, Pediatr
has been on the rise from 200 cases in year 1990 to
Infect Dis J and Int J Dermatol.
5107 cases in the year 2000 (Nissaptorn, et al., 2004).
Results: Based on our review, candidiasis can be
HIV patients are always associated with opportunistic
sub-divided into localized (oropharyngeal and
infections due to severely suppressed immunity.
vulvovaginal) and systemic candidiasis. Fluconazole is
These opportunistic infections are caused by virus,
found to be the most common used due to its high
bacteria, parasites, and fungal. Fungal infections are
efficacy treating candidiasis. Prophylaxis of
common in tropical country like Malaysia. Among the
crytococcal meningitis can be done by administering
most common fungal infections are candidiasis which
ketoconazole or itraconazole depending on whether it
is normally caused by Candida albicans, cryptococcal
is primary or secondary prophylaxis. Treatment using
meningitis which is caused by Cryptococcus
flucytosine in combination with amphotericin B has
neoformans and histoplasmosis which is caused by
additive effect and appears to be the most effective
Histoplasma capsulatum.
regimen for cryptococcal meningitis therapy.
Efficacy of a drug is the capability of a drug to produce
Histoplasmosis is characterized by pulmonary and
a positive effect. It is important to identify the site of
disseminated histoplasmosis and the mainstrays of
infection before a drug therapy can be administered.
therapy for histoplasmosis are amphotericin B and
Each drug and different dosage forms lead to
itraconazole. The most prominent side effects of
differences in efficacy on the particular disease. The
amphotericin B include nephrotoxicity, acute toxicity
efficacy of the drug must be taken into consideration
and hypokalemia. Flucytosine and itraconazole
so that the drug therapy is effective.
induces gastrointestinal side effects and bone marrow
Safety of a drug covers the aspects drug-drug
depression while hepatotoxicity is found to be the
interaction and side effects of the drugs. Most of the
major side effect of flucytosine and ketoconazole.
antifungal has adverse effects to certain extent. The
Ultimate care must be taken when administering
patient’s medical condition must be monitored before
ketoconazole as it has considerable drug interactions
administering the drugs. Besides, health professionals
with other medications. In patients treated with
must be aware of the other drug therapy that the HIV
fluconazole, the most common adverse effects include
patients are undergoing. This is due to susceptibility of
phlebitis, headache and nausea, abdominal pain,
the patients towards other opportunistic infections.
diarrhoea and rashes.
Our objectives are to compare the efficacy and safety
Conclusions: From our review, it appears to have
of the antifungal available for the three most common
different drug of choice of antifungals for different
opportunistic fungal infections in HIV patients.
opportunistic fungal infections. Besides, it is found that
different efficacy of different drugs form the basis Candidiasis
guideline for the therapeutic regimen in treating
opportunistic fungal infections. However, therapeutic
regimens recommended also induce various types of
The clinical manifestations of Candida infections can
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be from mucocutaneous to life-threatening invasive nystatin suspension or pastilles, or once-daily micon-
candidiasis (Zawadka & Marczynska, 2010). Common azole mucoadhesive tablets (Van, et al., 2004).
types of opportunistic infections caused by candida Posaconazole oral solution has similar effectiveness
species among the HIV patient in Malaysia can divided as fluconazole and is generally better tolerated than
into two main types, namely the localized candidiasis itraconazole. Posaconazole is proven more effective
and the systemic candidiasis. The most common than fluconazole to sustain clinical success after the
localized candidiasis is the oropharyngeal and anti-fungal therapy is discontinued (Vazquez, et al.,
vulvovaginal candidiasis. The systemic candidiasis is 2006).
oesophagitis candidiasis (Kaplan, et al., 2009). Topical non-absorbed therapy using the ‘swish and
The clinical manifestation of oropharyngeal candidiasis swallow’ principle is usually effective and is used in
is painless, creamy whitem plaque-like lesions of the patients with single occurrence of oropharyngeal
buccal or oropharyngeal mucosa or tongue surface. candidiasis as first-line therapy for 10-14 days. Local
Vulvovaginal candidiasis is characterized by the therapy consists of amphotericin B suspension or
burning and itching sensations of the vagina. It can tablets, nystatin lozenges or clotrimazole troches. A
also characterized by the curdy and thick vaginal study found that clotrimazole troches are as effective
discharge. Oesophageal candidiasis results in as itraconazole oral solution (Linpiyawan, Jittreprasert
retrosternal burning pain or discomfort and & Sivayathorn, 2000).
adynophagia (Kaplan, et al., 2009). A comparative study of itraconazole oral capsules
i.Localized Candidiasis (200mg once daily) and clotrimazole troches (10mg
a.Oropharyngeal candidiasis (OPC) five times daily) have same therapy effect.
Early stage and uncomplicated oropharyngeal Itraconazole has faster response and clotrimazole has
candidiasis can be treated with topical clotrimazole faster relapse rate (Blathford, et al., 1990). However,
troches or oral polyenes such as nystatin or fluconazole capsules are more effective than nystatin
amphotericin B suspension (Rex, et al., 2000). and at least equivalent to clotrimazole for thrush
In infants, troches should not be given because therapy (Pons, Greenspan & Debruin, 1993; Pons, et
resistance to clotrimazole can be developed easily if al., 1997).
they are exposed to azole drugs. The developed b.Vulvovaginal Candidiasis
resistance is related to refractory mucosal candidiasis Vulvovaginal candidiasis occurs in HIV-infected
(Pelletier, et al., 2000). For initial treatment of OPC, women and is usually uncomplicated (90%) and
systemic therapy with oral azoles such as fluconazole, responds to rapid oral or topical therapy including oral
ketoconazole or itraconazole is also effective (Pons, fluconazole, topical azoles (clotrimazole, butaconazole,
Greenspan & Debruin, 1993; Pons, et al., 1997). miconazole, ticonazole or terconazole) and
Fluconazole is more effective than nystatin suspension itraconazole oral solution. Severe or recurrent of
for initial treatment. Oral fluconazole is more suitable vaginitis needs the treatment of oral fluconazole or
for children than topical treatment (Pons, Greenspan & topical antifungal therapy for at least one week
Debruin, 1993; Goins, et al., 2002). (Kaplan, et al., 2009).
Itraconazole oral solution and fluconazole have similar Imidazole treatment is effective against C. glabrata
efficacy for one to two weeks but the former is less infections (Sobel, 1985). Strains resistant to
well tolerated than the latter (Phillips, et al., 1998; ketoconazole or fluconazole have been described
Vazquez, et al., 2006). Itraconazole should be taken in (Warnock, 1988), causing refractory cases. On the
the absence of food because gastric acid will enhance other hand, fluconazole is specific for C. albicans than
absorption of itraconazole. There are two dosage other imidazoles (Liss & Letourneau, 1989).
forms of itraconazole: capsules and oral solution. ii.Systemic disease of oesophagus
These two should not be used interchangeably a.Candida oesophagitis
because at the same dose, oral solution has more There is one prospective trial comparing two oral
drug exposure than that of capsules and absorption of agents: fluconazole (100-200mg qid) and
capsule formulation varies (Mofenson, et al., 2009). ketoconazole (200-400 mg qid) in 169 patients. Result
In adult, oral fluconazole is effective for topical therapy shows fluconazole has higher rates of endoscopic
for oropharyngeal candidiasis. It is because it is better (91% vs. 52%) and clinical (85% vs. 65%) cure than
to be tolerated and more convenient usage. Thus, oral that of ketoconazoles (Lame, et al., 1992). Since AIDS
fluconazole becomes the drug of choice for patients have decrease gastric acid secretion,
opopharyngeal candidiasis (Pappas, et al., 2004). (Dieterich & Rahmin, 1991) the difference of efficacy is
Same as infant, initial treatment for adults can be because of ketoconazole requires acid for absorption
treated by topical therapy such as clotrimazole troches, but not for fluconazole (Blum, et al., 1991).
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Amphotericin B is effective at relatively low doses in patients in Africa and also Southeast Asia (Holmes, et
Candida oesophagitis (0.3 mg/kg/day for a total dose al., 2003; Chariyalertsak, et al., 2001a). It often affects
of less or equal to 500 mg (Parente, et al., 1991). patients with weak immune system such as patients
An addition of new azoles such as voriconazole and with diabetes, lymphoma and AIDS (Dugdale, et al.,
posaconazole and also a new class of drug, the 2010). Commonly, cryptococcal meningitis is often
echinocandins (caspofungin, micafungin and associated with Human Immunodeficiency Virus (HIV)
anidulafungin) have provided more drug of choice to patients whereby their T-helper CD4 counts is less
treat opportunistic fungal infection (Kofla & Ruhnke, than 100 cells/µL (Bicanic & Harrison, 2004). Upon
2005; Nagappan & Deresinski, 2007; Metcalf & clinical presentation for acute onset (less than 7 days)
Dockrell, 2007). There are limited studies that report and chronic onset (more than 30 days), patients
the usage of agents in oesophageal candidiasis and usually present with fever, malaise, headache, having
their efficacy in other settings (condition) in HIV patient altered mental status and nuchal pain suggesting
(Ally, et al., 2001; Vazquez, et al., 2006; Villanueva, et meningeal irritation (Bicanic & Harrison, 2004;
al., 2002; Krause, et al., 2004; de Wet, et al., 2004). Subramanian & Mathai, 2005). Basically, primary
Echinocandins have limited drug interactions and prophylaxis is not necessary for cryptococcal
adverse effect, and therefore is used in severely ill meningitis since antifungal prophylaxis is not to be
patients. They are also good drug choices for hepatic used routinely to prevent cryptococcosis due to rarity
and renal dysfunction patients. According to of the disease, lack of survival benefit, possibility of
HIV-specific data, usage of echinocandin is limited to drug interaction and potential development of
HIV-seropositive individuals (Metcalf & Dockrell, antifungal drug resistance. Nevertheless, life-long
2007). secondary prophylaxis after completion of the initial
Systemic antifungals are used to treat oesophageal treatment regimen is indicated (Powderly, et al., 1996)
candidiasis effectively (Migliorati, et al., 2004). and recommended for patients who have completed
Fluconazole given orally or intravenously or oral initial therapy for cryptococcal infection (French, et al.,
itraconazole solutions, administered for 2 to 3 weeks, n.d.).
are highly effective for treatment of Candida
i. Treatment
esophagitis (Wilcox, et al., 1997). Voriconazole or
a. Amphotericin B
caspofungin are also effective in treating esophageal
candidiasis in HIV-infected adults. They must be In 1950s, treatment using Amphotericin B (a polyene)
administered intravenously due to limited was known to be the first effective therapy for
bioavailability (Mora-Duarte, et al., 2002; Walsh, 2002; non-HIV-associated infection. However amphotericin B
Deresinski & Stevens, 2003). is a concentration-dependent drug (Dodds, Drew &
Although IV caspofungin or IV voriconazole are Perfect, 2000) whereby studies on 0.7 mg/kg/day
effective in treating esophageal candidiasis among Amphotericin B regimen produces greater
HIV-infected patients, instead oral or IV fluconazole improvement outcome compared to 0.3-0.5 mg/kg/day
remains the preferable therapies (Migliorati, et al., in 10 weeks of therapy (Van Der Horst, et al., 1997).
2004). Two additional parenteral echinocandins Recommended dose for amphotericin B is 0.7-1.0
(micafungin and anidulafungin) are also approved to mg/kg/day and it is administered through intravenous
treat esophageal candidiasis. Although the three infusion. Further studies showed that the
echinocandins have similar efficacy as fluconazole, administration of high dose amphotericin B at 1
they all have a greater relapse rate compared with mg/kg/day with or without flucytosine for 2 weeks
fluconazole (de Wet, et al., 2004; Krause, et al., 2004). follow by consolidation therapy using itraconazole or
fluconazole had produced a positive outcome whereby
Cryptococcal Meningitis
94% (29 out of 31) patients survive cryptococcal
infection with zero mortality rates (DeLalla, et al.,
1995). Liposomal amphotericin B acts as an
Cryptococcal meningitis is the infection of the alternative lipid formulation, delivering of larger doses
meninges of the brain which is caused by of amphotericin B simultaneously giving same
encapsulated yeast Cryptococcus neoformans effectiveness while less nephrotoxicity comparing to
(Casadevall & Perfect, 1998) that is widely distributed conventional amphotericin B. From a randomized
and can be found in typical soil (Dugdale & Vyas, study, the rate of culture of conversion of the
2010). Cryptococcal meningitis is a common Cerebrospinal Fluid (CSF) was higher when
opportunistic in immuno-compromised patients such administrating liposomal amphotericin B at 4
as Acquired Immunodeficiency Syndrome (AIDS) mg/kg/day rather than the conventional amphotericin B
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(Leenders & Reiss, 1997). fluconazole, same outcome goes to another study
regarding the maintenance therapy (Bicanic &
b. Flucytosine
Harrison, 2004). Clinical study also showed
F lucytosine is often prescribed along with
fluconazole was 15% more effective than itraconazole
amphotericin B but not alone due to the development
in terms of CSF sterilization (Levitz, et al., 1999). A
of resistance in mono-therapy of flucytosine (Bicanic &
further study comparing efficacy using lower dose of
Harrison, 2004). It is proven that the combination of
fluconazole with itraconazole at 200 mg/day
amphotericin B (0.7 mg/kg/day) with flucytosine (150
respectively is conducted whereby the outcome
mg/kg/day) will lead to an additive effect (Bicanic &
appears to be proving fluconazole is superior in
Harrison, 2004; Medoff, Comfort & Kobayashi, n.d.;
maintenance therapy of cryptococcal infection (Bicanic
Block & Bennet, n.d.) as shown in clinical trials and
& Harrison, 2004; Van Der Horst, et al., 1997).
also pre-clinical studies in both HIV and non-HIV
ii. Prophylaxis
associated infection patients and eventually resulting a
successful treatment (Bicanic & Harrison, 2004; a. Primary
Larsen, Leal & Chan, 1990). However, there is another
Primary prophylaxis with azole antifungals has
studies conducted whereby the combination of
been observed to be effective in lowering the
amphotericin B with flucytosine (up to 75-100
incidence rate of cryptococcal meningitis in those with
mg/kg/day) did not change the survival of patients with
advanced HIV infection (Chariyalertsak et al., 2001b;
Acquired Immunodeficiency Syndrome (AIDS) and
Powderly, 1995; Mckinsey, Wheat & Cloud, 1999).
cryptoccocal disease compared to mono-therapy using
However, primary prophylaxis for cryptococcal
amphotericin B (Menichetti, Fiorio & Tosti, 1996).
meningitis is not recommended in developed countries
Therefore, combination of amphotericin B with
due to the lack of evidence of any survival bene?t, the
flucytosine and amphotericin B alone has been utilized
cost and the risk of promoting fungal resistance
whereby the findings appear to be an exponential
(Masur, Kaplan & Holmes, 2002).
decrease in CSF cryptococcal colony-forming units
It is concluded by studies that ketoconazole can be
(CFUs) (Brouwer, et al., 2004).
used as primary prophylactic agent against
c. Fluconazole
Cryptococcal meningitis and it was effective. The
Regarding the efficacy of fluconazole, comparative application of this agent may be very useful to
clinical trial shows that not much significant decrease developing countries, because of the price issue
in term of the efficacy when treatment is conducted where it is cheaper than other amidazoles,
using amphotericin B at 0.4-0.5 mg/kg/day and ultraconazole and fluconazole, and much easier to
fluconazole at 200 mg/day, a lower dose compared to take as compared to amphotericin B (Sprinz & Matias,
current recommended dose (400 mg/day), yielding a 1992).
result for negative culture of the CSF by 40% vs 34%
b. Secondary
and 14% vs 18% of rate of mortality for 10 weeks
Secondary propfhylaxis with fluconazole and
(Saag, et al., 1992). Comparing amphotericin B with
itraconazole are effective at preventing cryptococcal
fluconazole, clinical study shows that amphotericin B
meningitis in HIV-positive adults (Moosa & Coovadia,
has a shorter median time for the CSF sterilization,
n.d.; Kaplan et al., n.d.; Lopez et al., n.d.; El-Sadr et
which are 42 instead of 64 days (Saag, et al., 1992).
al., n.d.; Chariyalertsak et al., 2001b) but are only
Fluconazole also plays an important role in
associated with a survival benefit in patients with
consolidation therapy phase. Clinical study reviewed
either very low CD4 counts (
that a 2 weeks of induction therapy phase using
amphotericin B at 0.7 mg/kg/day, with or without Contrasting between itraconazole and
flucytosine at 100 mg/kg/day follow by consolidation fluconazole, secondary prophylaxis with itraconazole
phase using fluconazole or itraconazole at 400 mg/day is less effective in reducing relapses of successfully
for 6-8 weeks forms a good regimen combination treated cryptococcal meningitis over 12 months in
whereby having the rapid initial action of amphotericin people with HIV infection (BMJ publishing group,
B and a prolonged therapy using an azole that can 2008). Simultaneously, another study in Thailand has
prevent toxicity of amphotericin B in a long term also indicated that itraconazole prophylaxis at 200
therapy. mg/day significantly reduced the risk of invasive fungal
infections in those with advanced HIV disease (CD4
Itraconazole serves as an alternative oral agent.
counts less than 100 cells/ml) but did not result in
However, the CSF sterilization in 10 weeks during
improved survival (Subramanian & Mathai, 2005).
consolidation phase is found to be less effective than
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Histoplasmosis Patients with symptomatic disseminated
histoplasmosis are able to recover from the infection
without antifungal therapy in some extent, but this is
abnormal. Generally, all patients with disseminated
Histoplasmosis is and illness of infection resulting from
histoplasmosis should be treated with an antifungal
infection with the fungus which is Histoplasma
agent. Patients who are not severely ill can be treated
capsulatum. This infection can produce a spectrum of
with oral itraconazole of 200 mg twice daily.
illness, from subclinical infection to progressive
Fluconazole is less effective than itraconazole and is
disseminated disease. Opportunistic histoplasmosis
considered to be a second-line agent. The dosage of
develops as chronic pulmonary histoplasmosis in
fluconazole is 400 to 800 mg daily when it is used. In
those with a structural defect in the lung or as
AIDS patients, the dosage should be 800 mg daily
disseminated (progressive or spread) histoplasmosis
because of a failure rate of 50% in a cohort who had
in patients with cellular immune deficiency (due to
mild to moderately severe disseminated
immunosuppressants or HIV infection). In
histoplasmosis and who was treated with 600 mg daily.
disseminated disease, the infection can spread from
Patients with severe disseminated infection should be
lung to other organ via bloodstream. Untreated, this
treated initially with amphotericin B at a dosage of 0.7
latter form of infection may be rapidly fatal (Bradsher,
to 1 mg/kg daily or a lipid formulation of amphotericin
1996).
B at a dosage of 3 to 5 mg/kg daily. Lipid formulations
i.Pulmonary histoplasmosis of amphotericin B are used in most patients because
Chronic cavitary disease can result in significant loss of their reduced toxicity (Kauffman, 2007).
of lung function especially in patients with underlying iii.Treatment
structural lung disease. In cases of acute disease with
Amphotericin B in the form of intravenous infusion is
only mild to moderate symptoms, treatment is not
effective in histoplasmosis and because of its low
recommended because more than 95% of patients
toxicity and should be expected to be effective in
improve without therapy within 3 weeks. If symptoms
human histoplasmosis and it is proven to be the first
do not improve after 1 month, a 6 to 12 weeks course
effective treatment for histoplasmosis (Baum, Schwarz
of itraconazole is recommended. A lipid formulation of
&Wang, 1957).
Amphotericin B is preferred and should be given for
Itraconazole has been effective in primary as well as
the initial 1 to 2 weeks of treatment, followed by
chronic suppressive treatment of histoplasmosis in
itraconazole to complete a 3 month course of therapy.
patients with AIDS. In addition, in the treatment of
If patients have acute respiratory distress symptoms,
non-AIDS-associated progressive disseminated
Methylprednisolone is indicated for the first 1 to 2
histoplasmosis, itraconazole has been shown to be
weeks of therapy. This treatment is usually effective,
effective in cases of chronic pulmonary histoplasmosis,
although relapse occurs in up to 15% of patients. As a
although a relatively high relapse rate can be expected,
result of histoplasmosis complication, mediastinal
similar rates of relapse have been associated with
granuloma is developed. Itraconazole therapy is
amphotericin B therapy as well (Bradsher, 1996).
reasonable for symptomatic patients, and surgery is
However, some patients are unable to tolerate
an option for patients who do not respond to
itraconazole or are at risk for significant drug
pharmacological treatment. Pulmonary nodules
interactions. Therefore, alternative forms of therapy
(histoplasmomas) occur at sites that are previously
are required (McKinsey et al., 1996).
affected by Histoplasma and normally enlarge or
Fluconazole is a broad-spectrum triazole antifungal
cavitate slowly. If patients have multiple nodules,
drug that possesses in vitro activity against
acute pulmonary histoplasmosis is suspected and
Histoplasma capsulatum and has been effective in
must be treated. If hemodynamic compromise occurs,
both immunocompetent and immunosuppressed
effusion drainage will be required. Antifungal agents
murine models of histoplasmosis. Fluconazole has
are needed when corticosteroids are used whereby
been modestly effective as induction therapy and
itraconazole should be given.
maintenance therapy for disseminated histoplasmosis
Finally, arthritis and arthralgias may be resulted from
in patients with AIDS, and non-HIV-infected patients
an inflammatory complication of acute pulmonary
have also been treated successfully. Fluconazole
histoplasmosis. Erythema nodosum can occur as well.
remains a secondline agent for the treatment of
NSAIDs help in recovery, although corticosteroids may
histoplasmosis (McKinsey et al., 1996).
be required in the setting of severe disease, whereby
Ketoconazole is less toxic compare to amphotericin B.
itraconazole should be given as well (Duane, 2009).
In cases of chronic pulmonary histoplasmosis,
ii.Disseminated Histoplasmosis
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ketoconazole have been shown to be effective, How to overcome?
although a relatively high relapse rate can be expected Since the vasoconstrictive effects of Amphotericin B
similar rates of relapse have been associated with are clearly calcium dependent, it makes sense to
amphotericin B therapy as well (Bradsher, 1996). hypothesize that calcium channel antagonists might
In summary, fluconazole therapy was only moderately reduce Amphotericin B nephrotoxicity.
effective for treatment of chronic pulmonary
ii.Flucytosine
histoplasmosis and disseminated histoplasmosis at
Gastrointestinal Side Effects
the doses studied, but it was highly effective in the two
Side effects reported while taking flucytosine include
patients who had progressive acute pulmonary
diarrhoea, nausea, vomiting and diffuse abdominal
histoplasmosis. The previously reported efficacy of
pain (Benson & Nahata, 1988). Besides that, liver
itraconazole therapy for histoplasmosis in
enzymes also marked an increased in level but
non-HIV-infected patients is superior to the efficacy of
normally can be overcome by reducing the dose of
fluconazole observed. The use of fluconazole for
flucytosine. In addition, increase in concentration of
treating histoplasmosis in non-HIV-infected patients is
bilirubin in serum also noted in patient taking
to be reserved for mild to moderate disease in the
flucytosine but can be reversed by terminating
following patients those who cannot take itraconazole
administration of flucytosine (Scholer, 1980).
because of its toxicity, those with impaired absorption
Bone Marrow Depression
due to achlorhydria, or those receiving drugs that may
Bone-marrow depression rises to be the most severe
potentially interact with itraconazole. Multiple
toxicity caused by flucytosine. Several severe and
antifungal agents are available for histoplasmosis, but
life-threatening pancytopenias have been reported
amphotericin B and itraconazole are the mainstays of
associated with intake of flucytosine (Kauffman &
therapy.
Frame, 1977; Schlegel et al., 1970; Meyer & Axelrod,
Comparison of Safety 1974).
Hepatotoxicity
Flucytosine is concentration-dependent drug. Cases
i.Amphotericin B such as swelling of liver has been reported rarely
Acute toxicity (Scholer, 1980). However, hepatotoxicity is avoidable
Amphotericin B had more side effects of acute by maintaining peak concentration of flucytosine below
infusion-related reactions includes nausea, vomiting, 100 mg/L and is reversible by reducing the dose or
rigors, fever, hypertension or hypotension and hypoxia termination of therapy using flucytosine (Francis &
than those receiving other antifungal drugs. These Walsh, 1992; Stamm et al., 1987).
side effects were observed most frequently at the time How to overcome?
of the first infusion and disappeared during Adverse reactions and side effects of flucytosine can
subsequent infusions. These clinical side effects of be overcome by monitoring the serum drug
amphotericin B have been partially explained by the concentrations. For patients with renal failure or taking
release of interleukin-1, prostaglandin E-2, and tumor nephrotoxic drugs, or having gastrointestinal or
necrosis factor in response to amphotericin B haematological toxicity, therapeutic drug monitoring
administration (Pathak, et al., 1998). (TDM) and dosage adjustment is vital (Benson &
Nephrotoxicity Nahata, 1988).
Amphotericin B nephrotoxicity is caused by enhanced iii.Fluconazole
tubuloglomerular feedback. Tubuloglomerular Clinical adverse effect
feedback is a normal intrarenal mechanism whereby The clinical adverse effects of fluconazole are phlebitis,
increased solute delivery to the distal tubule results in headache and nausea, abdominal pain, diarrhoea and
afferent arteriolar vasoconstriction. Amphotericin B, rash. According to the study, the most common clinical
possibly because of its effects on biologic membranes, adverse effect is phlebitis. The only severe
increases monovalent ion delivery to the distal tubule, drug-related adverse event was cellulitis causing
causing afferent arteriolar vasoconstriction, most likely fluconazole infusion is more difficult to be administered
due to local adenosine release (Anderson, 1995). to the patient (Villaneuva, A. et al. 2002).
Hypokalemia Skin problem
In patients receiving amphotericin B, there also was a skin rashes can occur and severe skin condition like
greater frequency of moderate hypokalemia and Steven Johnson’s syndrome and exfoliative disorder
severe hypokalemia. Hypokalemia occurred more are reported.
often with higher amphotericin B doses.
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Laboratory adverse effects One-third of ketoconazole-induced hepatitis cases are
The laboratory adverse effects are decreased white accompanied by anorexia, malaise, vomiting and
blood counts, hemoglobin levels, and serum albumin nausea (Lewis, et al., 1984).
concentrations (Villaneuva, A. et al. 2002). Toxicity due to low albumin level
Hepatobiliary adverse effects Since ketoconazole is highly plasma protein bound
There is temporary elevation of liver enzymes and the (83.7%), it should be used with caution for the patients
severity varies among patients. The worst condition is who are malnutrition (Daneshmend & Warnock, 1988).
that it may lead to fatality due to liver failure. There are Patients who are malnutrition will not have sufficient
also increase of serum levels of enzymes like alkaline protein to distribute the drug and this will results in
phosphatase and aminotransferase (Villaneuva, A. et toxicity of the free, unbound drug in the body.
al. 2002).
Steroid synthesis blocker
How to overcome? Ketoconazole blocks the cortisol response to
Administer fluconazole orally often produces gastric adrenocorticotropic hormone significantly 4 hours after
irritation, heartburn and vomiting, ulceration 400mg/600mg dose. This inhibition lasts for 8 to 16
development and causes patients are less compliance hours. These findings showed that ketoconazole
with long term therapy. To minimize these side effects, reduces the adrenal androgen response.
topical admininisation of fluconazole in cutina lipogel Ketoconazole must be used with caution when it is
and gel microemulsion has been studied (El-laithy & used in high or multiple dose as it is a powerful steroid
El-Shaboury, 2002). The application of emulsions as synthesis blocker (Pont, et al., 1982).
topical drug carrier systems for the percutaneous
Drug-drug interaction
absorption of fluconazole has been investigated (Ayub,
Ketoconazole has significance drug interactions with
et al., 2007).
warfarin, chlordiazepoxide, methylpredisolone,
iv.Itraconazole
cyclosporine and microsomal enzymes inducing drugs
Hepatotoxicity
(Daneshmend & Warnock, 1988).
Itraconazole has been associated with rare cases of
How to overcome?
serious hepatotoxicity, including liver failure and death.
In order to overcome all these problems, dose
Some of these cases had neither pre-existing liver
adjustment must be made and drug monitoring must
disease nor a serious underlying medical condition. If
be done accordingly.
clinical signs or symptoms develop that are consistent
with liver disease, treatment should be discontinued Conclusion
and liver function testing should be performed.
Gastrointestinal
Common adverse effects of itraconazole therapy
HIV patients are often associated with opportunistic
include gastrointestinal effects diarrhoea, skin rash,
infections due to their weakened body immunity
and reversible increases in hepatic enzymes. Less
system. In this case, we focused on three fungal
common but more severe side effects such as
infections such as candidiasis, cryptococcal meningitis
congestive heart failure and idiosyncratic hepatic
and histoplasmosis which appear to be the most
failure have been reported.
common opportunistic infections in HIV patients. From
How to overcome? our study, common antifungals used are amphotericin
In general, use of itraconazole should be avoided with B, flucytosine, fluconazole itraconazole and
severe liver disease patients. However, if itraconazole ketoconazole and it appears to have different drug of
is used, concurrent monitoring of itraconazole levels choice of antifungals for different opportunistic fungal
along with hepatic enzymes and billirubin may be infections in HIV patients. Besides, it is found that
prudent given that liver disease is associated with different efficacy of different drugs form the basis
multiple factors such as protein binding, drug guideline for the therapeutic regimen in treating
distribution that can affect drug distribution and opportunistic fungal infections.
clearance (Lewis and Prince, 2001). However, those therapeutic regimens recommended
v.Ketoconazole also induce various types of adverse reactions or side
Hepatotoxicity effects such as nephrotoxicity, gastrointestinal side
33 out of 54 cases in an US study show effects and hepatotoxicity. Therefore, dose adjustment
ketoconazole-induced hepatitis whereby women of and therapeutic drug monitoring must be performed
age more than 40years old are more likely to be accordingly and routinely to avoid unnecessary
affected. 27 people in that study had jaundice. complications.
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Acknowledgment 12.Brouwer, A.E., Rajanuwong, A., Chierakul, W. et al.
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No sources of funding are used to assist in preparing
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through University Sains Malaysia. The authors are
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grateful to Dr Amin Malik Shah Abdul Majid for giving
O. et al. 2001. Clinical presentation and risk behaviors
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