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. WebmedCentral > Review articles Page 1 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM 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 WebmedCentral > Review articles Page 2 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM 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). WebmedCentral > Review articles Page 3 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM 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 WebmedCentral > Review articles Page 4 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM (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 WebmedCentral > Review articles Page 5 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM 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 WebmedCentral > Review articles Page 6 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM 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. WebmedCentral > Review articles Page 7 of 13 WMC002674 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:45:22 PM 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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