March 12, 2007

Ureaplasma Urealyticum

What is ureaplasma urealyticum?

Ureaplasma urealyticum is a bacterial infection, which can cause non-specific urethritis (NSU) in men.

What are the symptoms?

Roughly a third of men with NSU have no symptoms. Those who do experience symptoms get:

  • Cloudy discharge when they urinate
  • Stinging or burning when they urinate

What causes it?

  • Ureaplasma urealyticum is found in the semen of up to 40% of men.
  • Any form of sexual contact can cause the bacterium to spread, therefore wearing a condom can protect you against it.
  • The infection can also be transferred on sex toys.
  • It cannot be transferred on toilet seats, towels or when shaking hands.

Who is at risk?

Ureaplasma urealyticum is thought to be responsible for up to 20% of all cases of NSU in men.

Those most at risk are gay men aged 20 to 35.

Diagnosis and treatment

If you think you've been infected, visit your GP or genito-urinary medicine (GUM) clinic immediately. They will:

  • Examine your genital area and swab it for a specimen
  • Ask for a urine sample
  • Prescribe antibiotics to clear it up
  • Avoid sexual contact during treatment and inform any sexual partners, so they can also be treated

March 11, 2007

Candidiasis

Synonyms and related keywords: candidosis, candidal infection, fungal infection, fungus infection, Candida, mucocutaneous candidiasis, candidemia, disseminated candidiasis, candidal colonization, candidiasis syndromes, intertrigo, paronychia, onychomycosis, oral thrush, fungi, fungal pathogens, mucosal candidiasis, systemic candidiasis, hepatosplenic candidiasis, Candida peritonitis, fungemia, life-threatening invasive candidiasis, opportunistic nosocomial fungal infections, yeastlike fungi, granulocytopenia, bone-marrow transplantation, solid-organ transplantation, parenteral hyperalimentation, hematologic malignancies, Foley catheters, solid neoplasms, recent chemotherapy, recent radiation therapy, corticosteroids, broad-spectrum antibiotics, burns, prolonged hospitalization, severe trauma, recent bacterial infection, recent surgery, gastrointestinal tract surgery, central intravascular access devices, premature birth, hemodialysis, oropharyngeal candidiasis, OPC, indwelling vascular devices, collagen-vascular disease, esophageal candidiasis, Candida esophagitis, vulvovaginal candidiasis, VVC, cutaneous candidiasis syndromes, Candida folliculitis, diabetes mellitus, chronic mucocutaneous candidiasis, hypoparathyroidism, Addison disease, hypothyroidism, thymomas, dental dysplasia, polyglandular autoimmune disease, antibodies to melanin-producing cells, vitiligo, membranous candidiasis, erythematous candidiasis, chronic atrophic candidiasis, denture stomatitis, angular cheilitis, dysphagia, odynophagia, nonesophageal gastrointestinal candidiasis, respiratory tract candidiasis, laryngeal candidiasis, Candida tracheobronchitis, Candida pneumonia, genitourinary tract candidiasis, Candida balanitis, Candida cystitis, fungal balls, candidal endophthalmitis, intravascular catheter-related candidiasis, fungal endocarditis, Candida parapsilosis, renal candidiasis, fungal meningitis, granulomatous vasculitis, diffuse cerebritis with microabscesses, mycotic aneurysms, Candida arthritis, Candida osteomyelitis, Candida costochondritis, Candida myositis, Candida myocarditis-pericarditis, Candida splenic abscess, Candida hypersplenism, Candida cholecystitis, Candida albicans, C albicans, Candida glabrata, C glabrata, Candida tropicalis, C tropicalis, Candida krusei, C krusei, Candida kefyr, C kefyr, Candida dubliniensis, C dubliniensis, Candida guilliermondi, C guilliermondi, Candida lusitaniae, C lusitaniae


INTRODUCTION

Background: Candida species are ubiquitous fungi and are the most common fungal pathogens that affect humans. The growing problem of mucosal and systemic candidiasis reflects the enormous increase in the pool of patients at risk and the increased opportunity that exists for Candida species to invade tissues normally resistant to invasion. Candida species are true opportunistic pathogens that exploit recent technological advances to gain access to the circulation and deep tissues.

The increased prevalence of local and systemic disease caused by Candida species has resulted in numerous new clinical syndromes, the expression of which is primarily dependent on the immune status of the host. Candida species produce a wide spectrum of diseases, ranging from superficial mucocutaneous disease to invasive illnesses, such as hepatosplenic candidiasis, Candida peritonitis, and systemic candidiasis. Management of serious and life-threatening invasive candidiasis remains severely hampered by delays in diagnosis and the lack of reliable diagnostic methods that allow detection of both fungemia and tissue invasion by Candida species.

Advances in medical technology, chemotherapeutics, cancer therapy, and organ transplantation have had a major impact on reducing the morbidity and mortality of life-threatening disease. Patients who are critically ill and in medical and surgical ICUs have been the prime targets for opportunistic nosocomial fungal infections, primarily due to Candida species. Studies suggest that the problem is not under control and, in fact, show it is worsening. On a daily basis, virtually all physicians are confronted with a positive Candida isolate obtained from one or more various anatomical sites. High-risk areas for Candida infection include neonatal, pediatric, and adult ICUs, both medical and surgical. Candida infections can involve any anatomical structure.

Pathophysiology: Candida species are yeastlike fungi that can form true hyphae and pseudohyphae. For the most part, Candida species are confined to human and animal reservoirs; however, they are frequently recovered from the hospital environment, including on foods, counter tops, air-conditioning vents, floors, respirators, and medical personnel. They are also normal commensals of diseased skin and mucosal membranes of the GI, genitourinary, and respiratory tracts.

Candida species also contain their own set of well-recognized virulence factors. Although not well characterized, several virulence factors may contribute to their ability to cause infection. The main virulence factors are surface molecules that permit adherence of the organism to other structures (eg, human cells, extracellular matrix, prosthetic devices), acid proteases, and the ability to convert to a hyphal form.

As with most fungal infections, host defects also play a significant role in the development of candidal infections. Numerous host defects are associated with candidal infections.

Host defense mechanisms against Candida infection and their associated defects that allow infection are as follows:

Risk factors associated with candidiasis include the following:

The first step in the development of a candidal infection is colonization of the mucocutaneous surfaces. The factors outlined above are all associated with increased colonization rates. The routes of candidal invasion are (1) disruption of a colonized surface (skin or mucosa), allowing the organisms access to the bloodstream, and (2) persorption via the GI wall, which may occur following massive colonization with large numbers of organisms that pass directly into the bloodstream.

Frequency:

Mortality/Morbidity:

Sex: Colonization with Candida species occurs in equal numbers of males and females; however, in women, VVC is the second most common cause of vaginitis.

Age: Candidal colonization is at the highest levels during the extremes of ages, in neonates and in people older than 65 years. In addition, mucocutaneous candidiasis is also more prevalent in neonates and older adults.


CLINICAL

History: Infections due to Candida species can manifest in a wide spectrum of clinical syndromes as described below. The clinical presentation can vary depending on the type of infection and the degree of immunosuppression. Clinical syndromes associated with Candida infection are the following:

Cutaneous candidiasis syndromes

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis describes a group of Candida infections of the skin, hair, nails, and mucous membranes that tends to have a protracted and persistent course.

GI tract candidiasis

Respiratory tract candidiasis

The respiratory tract is frequently colonized with Candida species, especially in hospitalized patients. In ambulatory patients, 20-25% of the population is colonized by Candida species.

Genitourinary tract candidiasis

Hepatosplenic candidiasis

A variety of systemic candidiasis patients have an underlying hematologic malignancy and are in the recovery phase of a prolonged episode of neutropenia. The patient's history includes the following:

Physical examination findings include right upper quadrant tenderness and hepatosplenomegaly (less than 40%).

Systemic candidiasis

Systemic candidiasis can be divided into 2 major categories, which are candidemia and disseminated candidiasis (organ infection by Candida species). Deep organ infections due to Candida species are generally observed as part of the disseminated candidiasis syndromes, which may be associated with either single or multiorgan involvement.

  • Candidemia
    • Candida species currently are the fourth most commonly isolated organism in blood cultures, and Candida infection generally is considered a nosocomially acquired infection. The patient's history commonly reveals the following:
    • Physical examination is remarkable for the following:
      • Fever
      • Macronodular skin lesions (approximately 10%)
      • Candidal endophthalmitis (approximately 10-28%)
      • Occasionally, septic shock (hypotension, tachycardia, tachypnea)
    • Other causes of candidemia without invasive disease include the following:
      • Intravascular catheter-related candidiasis: This entity usually responds promptly to catheter removal and antifungal treatment.
      • Suppurative thrombophlebitis: For the most part, this is observed secondary to prolonged central venous catheterization. Suppurative thrombophlebitis manifests as fever and candidemia, which persist despite antifungal therapy and catheter removal. Sepsis also may be present.
      • Endocarditis: The frequency of endocarditis has increased in the past few years. Endocarditis is the most common cause of fungal endocarditis and is primarily due to Candida albicans (>60% of cases). The most common valves involved are the aortic and mitral. The 2 different forms of endocarditis are exogenous, which is secondary to direct infection during surgery, and endogenous, which is due to secondary spread during candidemia and disseminated candidiasis. Endocarditis is frequently associated with 4 main risk factors. These are (1) intravenous heroin use, which is frequently associated with infection due to Candida parapsilosis; (2) chemotherapy; (3) prosthetic valves (approximately 50%); and (4) prolonged use of central venous catheters.

        The physical examination in patients with endocarditis reveals a broad range of manifestations, which include fever unresponsive to antimicrobials, hypotension, shock, new or changing murmurs, and large septic emboli to major organs, a characteristic of fungal endocarditis.

  • Disseminated candidiasis: This is frequently associated with multiple deep organ infections or may involve single organ infection. Unfortunately, of patients with disseminated candidiasis, as many as 40-60% may have blood culture results negative for Candida species. The history of a patient with presumptive disseminated candidiasis reveals a fever unresponsive to broad-spectrum antimicrobials and negative results from blood culture. Physical examination reveals fever (may be the only symptom) with an unknown source and sepsis and septic shock.
  • Candida endophthalmitis: The 2 forms of Candida endophthalmitis are the exogenous form and the endogenous form. Exogenous endophthalmitis is associated with either accidental or iatrogenic (postoperative) injury of the eye and inoculation of the organism from the environment. Endogenous endophthalmitis results from hematogenous seeding of the eye. It is found in 10-28% of patients with candidemia. The use of hematogenous candidal endophthalmitis as a marker of widespread disseminated candidiasis is important.
    • The patient's history reveals a broad range of manifestations.
      • Eye injury
      • Ophthalmic surgery
      • Underlying risk factors for candidemia
      • Asymptomatic and detected upon physical examination
      • Ocular pain
      • Photophobia
      • Scotomas
      • Floaters
    • Physical examination reveals fever.
    • Upon funduscopic examination, early lesions are the size of a pinhead, are off-white in color, and are found in the posterior vitreous with distinct margins and minimal vitreous haze. Classic lesions are large and off-white, similar to a cotton-ball, with indistinct borders covered by an underlying haze. Lesions are 3-dimensional and extend into the vitreous off the chorioretinal surface. They may be single or multiple.
  • Renal candidiasis
    • This most frequently is a consequence of candidemia and disseminated candidiasis. Patient history includes fever that is unresponsive to broad-spectrum antimicrobials. Frequently, patients are asymptomatic and lack symptoms referable to the kidney.
    • Physical examination generally is unremarkable, and renal candidiasis is diagnosed after urinalysis and renal biopsy. Otherwise, this condition is commonly diagnosed at autopsy.
  • CNS infections due to Candida species
    • CNS infections due to Candida species are rare and difficult to diagnose. The 2 primary forms are exogenous infection and endogenous infection. Exogenous infection results from postoperative infection, trauma, lumbar puncture, or shunt placement. Endogenous infection results from candidemia, thus involving the brain parenchyma and multiple small abscesses (eg, disseminated candidiasis).
    • As with other organ infections due to Candida species, patients usually have underlying risk factors for disseminated candidiasis. CNS infections due to Candida species are frequently found in patients hospitalized for long periods in ICUs. The spectrum of this disease includes the following:
      • Meningitis
      • Granulomatous vasculitis
      • Diffuse cerebritis with microabscesses
      • Mycotic aneurysms
      • Fever unresponsive to broad-spectrum antimicrobials
      • Mental status changes
    • Physical examination reveals the following:
      • Fever
      • Nuchal rigidity
      • Confusion
      • Coma
  • Candida arthritis, osteomyelitis, costochondritis, and myositis
    • In the past, musculoskeletal infections were rare; currently, they are more common, due to the increased frequency of candidemia and disseminated candidiasis. The most common sites of involvement are the knee and vertebral column. The pattern of involvement is similar to the pattern observed in bacterial infections. The infection may be exogenous or endogenous. The exogenous infection is frequently due to direct inoculation of the organisms, such as postoperative infection or trauma. Affected sites include the following:
      • Ribs and leg bones (less than 20 y)
      • Vertebral column and paraspinal abscess (adulthood)
      • Flat bones (any age group)
      • Sternum - Generally observed postoperatively after cardiac surgery
    • The patient frequently is asymptomatic, and the patient's history reveals underlying risk factors of disseminated candidiasis and localized pain over the affected site. The physical examination frequently is unremarkable; otherwise, it may reveal tenderness over the involved area, erythema, and bone deformity, occasionally with a draining sinus.
      • Arthritis: Generally, arthritis is a complication of disseminated candidiasis, but it may be caused by trauma or direct inoculation due to surgery or steroid injections. Most cases are acute and begin as a suppurative synovitis. A high percentage of cases progress to osteomyelitis. In addition, developing Candida arthritis after joint replacement is not uncommon.
      • Osteomyelitis: The 2 forms of osteomyelitis are exogenous infection and endogenous infection. The exogenous infection is frequently due to either direct inoculation of the organisms, such as through postoperative infection, trauma, or steroid injections. The endogenous form of osteomyelitis generally is a complication of disseminated candidiasis. Most cases due to hematogenous seeding infect the vertebral disks and progress to diskitis with extension into the vertebrae from contiguous spread. Other bones affected include the wrist, femur, scapula, and proximal humerus.
      • Costochondritis: This is rare and usually has 2 forms. Costochondritis usually results from either hematogenous spread or direct inoculation during surgery (median sternotomy). Frequently, costochondritis is associated with localized pain over the involved area.
      • Myositis: This occurs infrequently, and an association with disseminated candidiasis is common. Most patients are neutropenic. People with myositis have a history of muscular pain.
  • Myocarditis-pericarditis: This is due to hematogenous spread in association with disseminated disease and is rarely due to direct extension from the sternum or esophagus. Myocarditis-pericarditis occurs as diffuse abscesses scattered throughout the myocardium with normal cardiac tissue. In persons with disseminated candidiasis, the rate has been documented to be as high as 50%. The patient history reveals serious complications in 10-20% of cases without valve disease and fever and chills. Physical examination reveals fever, hypotension, shock, tachycardia, and new murmurs or rubs (changes in previously detected murmurs).
  • Candida peritonitis
    • The patient history frequently reveals an association with GI tract surgery, viscous perforation, or peritoneal dialysis. Candida peritonitis tends to remain localized, and only in 15% of cases does the infection disseminate into the blood stream. The range of manifestations is broad and includes fever and chills, abdominal pain and cramping, nausea and vomiting, and constipation.
    • Physical examination is significant for the following:
      • Fever
      • Abdominal distention
      • Abdominal pain
      • Absent bowel sounds
      • Rebound tenderness
      • Localized mass
  • Candida splenic abscess and hypersplenism: Both are manifestations of disseminated candidiasis and are usually simultaneously associated with liver involvement. Manifestations of hypersplenism are common (see Hepatosplenic candidiasis).
  • Candida cholecystitis: This is rare and generally is associated with bacterial cholangitis and ascending cholangitis. Most commonly, Candida cholecystitis is diagnosed at the time of surgery when a culture is obtained.

Physical: See History for physical examination findings paired with clinical syndromes.

Causes: More than 100 species of Candida exist in nature; only a few species are recognized causes of disease in humans.

  • The medically significant Candida species include the following:
    • C albicans, the most common species identified (50-60%)
    • Candida glabrata (15-20%)
    • C parapsilosis (10-20%)
    • Candida tropicalis (6-12%)
    • Candida krusei (1-3%)
    • Candida kefyr (less than 5%)
    • Candida guilliermondi (less than 5%)
    • Candida lusitaniae (less than 5%)
    • Candida dubliniensis, primarily recovered from patients who are positive for HIV
  • C glabrata and C albicans account for approximately 70-80% of yeast isolated from patients with invasive candidiasis. C glabrata has recently become important because of its increasing incidence worldwide, and it is intrinsically less susceptible to azoles and amphotericin B.
  • C krusei is important because of its intrinsic resistance to ketoconazole and fluconazole (Diflucan); additionally, it is also less susceptible to all other antifungals, including itraconazole (Sporanox) and amphotericin B.
  • Another important Candida species is C lusitaniae; although not as common as some Candida species, it is of clinical significance because it is frequently resistant to amphotericin B, although it remains susceptible to azoles and echinocandins.
  • C parapsilosis is an important species to consider in hospitalized patients with vascular catheters.
  • C tropicalis has been considered an important cause of candidemia in patients with cancer (leukemia) and in those who have undergone bone marrow transplantation.


WORKUP

Lab Studies:

Imaging Studies:

Procedures:

Histologic Findings: Fixed tissues can be stained with hematoxylin and eosin. In addition, fungal hyphae may be demonstrated with Grocott silver-methenamine, methylene blue, or periodic acid-Schiff staining. The classic appearance demonstrates the Candida species as either round or ovoid yeast cells, hyphae, or pseudohyphae.


TRETMENT

Medical Care: Treatment of Candida infections varies substantially and is based on the anatomic location of the infection, the patients' underlying disease and immune status, the patients' risk factors for infection, the specific species of Candida responsible for infection, and, in some cases, the susceptibility of the strain to antifungal drugs. In January 2004, the Infectious Disease Society of America published updated practice guidelines for the treatment of candidiasis. These latest recommendations include newer antifungal agents, such as caspofungin and voriconazole, in several specific indications. The therapeutic options for the management of invasive candidiasis and candidemia continue to increase with the addition of newer echinocandins.

Surgical Care:

Consultations: In some forms of candidiasis, involving physicians of different specialties for some of the specific infections may be necessary. Some examples of these situations are endocarditis, endophthalmitis, peritonitis, osteomyelitis, and other forms of invasive candidiasis that may require surgical drainage and debridement.


MEDICATION

Successful therapy for serious systemic Candida infections requires starting antifungal therapy as early as possible. Treatment should be initiated as soon as adequate cultures are obtained. Four groups of antifungals can be used to manage candidal infections. Azoles have become the mainstay of therapy over the past few years. These include topical and systemic agents. Polyenes include amphotericin B, liposomal amphotericin B formulations, and topical nystatin. Allylamines include terbinafine, which is formulated in a topical preparation and an oral tablet. The newest are triazoles that include posaconazole.

Drug Category: Antifungal agents, triazole -- These agents inhibit fungal ergosterol synthesis. They are structurally similar to azoles but possess a single isomer and are not as extensively metabolized by CYP450 enzymes.

Drug Name
Posaconazole (Noxafil) -- Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Adult Dose 200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption
Pediatric Dose less than 13 years: Not established
>13 years: Administer as in adults
ContraindicationsDocumented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine) likely to result in serious toxicities
Interactions Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk); inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)
Pregnancy

C - Safety for use during pregnancy has not been established.

PrecautionsCommon adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding

Drug Category: Antifungals, azole -- These agents are synthetic compounds that include 2 groups, imidazoles and triazoles. Triazoles have 3 atoms of nitrogen in the azole ring. Imidazoles have only 2. The primary mechanism of action is inhibition of lanosterol 14-alpha-demethylase, an enzyme required for the synthesis of ergosterol, the main component of fungal cell membranes. Imidazole agents include miconazole, ketoconazole, and clotrimazole. Triazole agents, which are now the most commonly used azoles, include fluconazole, itraconazole, econazole, terconazole, butoconazole, and tioconazole. Newer azoles (ie, voriconazole, posaconazole, ravuconazole) are active against fluconazole-resistant strains of Candida. Voriconazole and posaconazole have shown high efficacy against candidiasis in recent clinical trials.

Topical agents are used to manage local forms of candidiasis such as cutaneous candidiasis, OPC, and VVC. These preparations are available as a cream for topical use, as troches for OPC, and as a vaginal suppositories or tablets for vaginitis.
Drug Name
Voriconazole (Vfend) -- Available in both oral and parenteral preparations. As active as fluconazole against esophageal candidiasis and is FDA approved for esophageal candidiasis and candidemia. In Europe, it has been approved for "treatment of fluconazole-resistant serious invasive Candida infections (including C krusei)."
Adult DoseLoading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; switch to 200 mg PO q12h when able to tolerate; may increase to 300 mg PO q12h if inadequate response
less than 40 kg: Average maintenance dose is 100 mg PO q12h (may increase to 150 mg PO q12h)
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; CrCl less than 50 mL/min (decreased excretion of IV vehicle) if administering IV; coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, or ergot alkaloids
InteractionsCYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady-state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids) and others may mandate more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG-CoA inhibitors, benzodiazepines, calcium channel blockers)
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsDecrease maintenance dose in hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorders; rare cases of severe hepatotoxicity reported; administer PO dose 1 h ac or pc
Drug Name
Fluconazole (Diflucan) -- Triazole with less effect on human sterol metabolism. Does not decrease cortisol and testosterone levels, as occurs with ketoconazole. Has fewer adverse effects and better tissue distribution than older systemic imidazoles. Available PO/IV and has demonstrated efficacy in topical and invasive forms of candidiasis. Available in 50-, 100-, 150-, and 200-mg tabs.
Daily dose varies with indication.
Adult DoseOropharyngeal and esophageal disease
100 mg/d PO/IV for 7-14 d
Candidemia and invasive candidiasis
800-mg loading dose, followed by 400 mg/d PO/IV; if C glabrata, dose should be 800 mg/d
Renal insufficiency
CrCl 25-49 mL/min: Decrease dose by 50%
CrCl less than 25 mL/min: Decrease dose by additional 75%
Hemodialysis
Usual daily dose after each dialysis
Bone marrow transplantation
200-400 mg/d PO/IV starting at time of bone marrow ablation and continuing until neutropenia resolves; recent studies seem to indicate continuing therapy for longer periods may decrease mortality in transplant recipients
Pediatric Doseless than 2 weeks: Administer q72h IV
>4 weeks: 3 mg/kg/d PO/IV for superficial infections and 6-12 mg/kg/d for systemic infections
ContraindicationsDocumented hypersensitivity
InteractionsInhibits cytochrome P450 hepatic enzymes to cause increased levels of atovaquone, AZT, benzodiazepines, clarithromycin, cyclosporine, oral hypoglycemics, phenytoin, rifabutin, saquinavir, tacrolimus, theophylline, terfenadine, and warfarin; levels may increase with hydrochlorothiazide; levels may decrease with long-term coadministration of rifampin, rifabutin, and phenytoin
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsNausea, vomiting, diarrhea, and allergic reactions are most common adverse effects; adjust dose for renal insufficiency; monitor closely if rash develops and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) and while taking multiple concomitant medications; not recommended during breastfeeding
Drug Name
Itraconazole (Sporanox) -- Has fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. Effective against broad range of fungi, including Candida species, and is indicated for treatment of cutaneous, oral, esophageal, and disseminated candidiasis.
Available IV, 100-mg caps, and oral solution at 10 mg/mL.
Caps require gastric acidity for absorption and should be taken with food to increase absorption. Liquid formulation increases bioavailability and decreases need for acidity for proper absorption.
Use of solution has been recommended in mucosal and invasive candidiasis, while caps can be used in onychomycosis and dermatophyte infections.
Adult DoseCutaneous candidiasis and onychomycosis: 200 mg PO/IV bid for 7 d/mo for 3-6 mo
OPC and esophageal candidiasis: 200 mg/d PO/IV for 7-14 d
Candidemia and invasive candidiasis: 200 mg tid for 3 d, followed by 200 mg PO/IV bid for 14-21 d
Pediatric DoseCutaneous candidiasis: 3-5 mg/kg/d PO/IV for 30 d
ContraindicationsDocumented hypersensitivity
InteractionsAntacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); inhibits cytochrome P450 hepatic enzymes to cause increased levels of atovaquone, AZT, benzodiazepines, clarithromycin, cyclosporine, digoxin, oral hypoglycemics, midazolam phenytoin, rifabutin, saquinavir, tacrolimus, theophylline, triazolam, and warfarin
Levels may decrease with long-term coadministration of rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine, and isoniazid; increases levels of indinavir, saquinavir, and ritonavir; indinavir, ritonavir, and fixed-dose combination of lopinavir/ritonavir increase levels
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in hepatic insufficiencies; nausea, vomiting, diarrhea, and abdominal discomfort may occur; high doses may produce hypertension, hypokalemia, or edema; may have negative inotropic effect; exacerbations of congestive heart failure reported, especially with IV administration
Drug Category: Antifungals, polyenes -- These are broad-spectrum, fungicidal agents. Mechanism of action is by insertion into fungal cytoplasmic membrane, causing increases in permeability. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.
Drug Name
Amphotericin B (Fungizone, Amphocin) -- One of the oldest antifungals, in use for more than 40 y, and the criterion standard of antifungal therapy.
In recent years, lipid formulations have been developed. Total dose must be adjusted depending on type of candidal infection being treated. Most patients receive total dose of 0.5-1.5 g.
Adult Dose0.3-1.5 mg/kg/d IV infused in 5% dextrose over 2-4 h; 10-mg lozenges or 1 mL of a 100-mg/mL solution PO qid
Candiduria: Continuous bladder irrigation at concentrations of 50 mg/L for 3 consecutive days
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity
InteractionsConcomitant administration of nephrotoxic antibiotics, cyclosporine, other nephrotoxic immunosuppressants, or parenteral pentamidine may lead to an increased risk of nephrotoxicity; may enhance effects of neuromuscular-blocking drugs; may increase toxicity of digitalis glycosides
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsInfusion-related toxicity includes acute reactions occurring approximately 30-45 min after beginning infusion; typically, patients have chills, fever, and tachypnea; premedication with acetaminophen or addition of hydrocortisone (25-50 mg) to infusion can diminish reactions; meperidine can shorten rigor; nephrotoxicity (approximately 30-40%); monitor patients receiving any parenteral form of amphotericin B for changes in renal function (BUN, serum creatinine), liver function, and serum electrolytes (eg, serum potassium, magnesium); nephrotoxicity may be decreased by administering 0.5-1 L of 0.9% NS 1-2 h prior to each infusion; normocytic normochromic anemia may develop, usually after 7-10 d of therapy; monitor CBC count with differential 3 times/wk
Drug Name
Amphotericin B, lipid formulations (Amphotec, Abelcet, AmBisome) -- Novel lipid formulations of amphotericin B that deliver higher concentrations of drug with a theoretical increase in therapeutic potential and decreased nephrotoxicity.
Formulation types include amphotericin B lipid complex (ABLC, Abelcet), amphotericin B colloidal dispersion (ABCD, Amphotec), and liposomal amphotericin B (L-AMB, AmBisome).
ABLC and ABCD approved for treating adults and children intolerant of conventional amphotericin B or with fungal infections refractory to conventional amphotericin B. L-AMB is approved for aspergillosis, candidiasis, cryptococcosis, and neutropenic patients with persistent fever on broad-spectrum antibiotics.
Adult DoseABLC: 5 mg/kg/d IV; duration of infusion 1-2 h
ABCD: 3-6 mg/kg/d IV; duration of infusion 1-2 h
L-AMB: 1-7 mg/kg/d IV; duration of infusion 1-2 h
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity
InteractionsAntineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digoxin, and thiazides may potentiate hypokalemia; risk of renal toxicity increased with cyclosporine
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsNephrotoxicity can occur with amphotericin B (approximately 30-50%), ABLC (approximately 25%), ABCD (approximately 20%), or L-AMB (approximately 20%); monitor BUN, serum creatinine, potassium, and magnesium levels daily; infusion-related toxicity can occur with amphotericin B (>50%), ABLC (approximately 30-50%), ABCD (>50%), and L-AMB (approximately 15-30%); manifestations include fever, chills, rigors, nausea, vomiting, hypertension, tachycardia, and hypoxia; elevations in hepatic transaminases, alkaline phosphatases, and serum bilirubin may occur
Drug Name
Nystatin (Mycostatin) -- Fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. Effective against various yeasts and yeastlike fungi. Changes permeability of fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.
Adult DoseVaginal candidiasis: 100,000 U vaginal tab; dissolve 1 tab hs for 14 d
OPC: 200,000 U pastille; dissolve 1-2 pastilles qid for 7-14 d; 100,000 U susp; 5 mL swish and swallow qid for 7-14 d
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy A - Safe in pregnancy
PrecautionsDo not use to treat systemic mycoses; adverse GI effects include nausea, vomiting, and diarrhea
Drug Category: Antimetabolite -- Flucytosine is an antimetabolite originally developed for the treatment of leukemia.
Drug Name
Flucytosine (Ancobon) -- It is deaminated to 5-fluorouracil in the fungal cell by an enzyme not present in mammalian cells, and inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B. It has been used in studies in invasive candidiasis. Avoid use as single agent because of ability to quickly develop resistance in vivo.
Adult Dose100-150 mg/kg/d PO divided q6h
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity
InteractionsAmphotericin B may increase toxicity; cytosine may inactivate flucytosine
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCommonly administered in combination with amphotericin B; overall toxicity approximately 30%; adjust dose to produce plasma concentration of 25-50 mcg/mL; myelosuppression associated with blood concentration >100 mcg/mL; adjust dose in renal impairment; CBC count with differential monitored 3 times/wk; occasional hepatotoxicity reported
Drug Category: Topical azoles -- These agents are used very extensively to treat common mucocutaneous, uncomplicated forms of candidiasis.
Drug Name
Clotrimazole (Mycelex, Femizole-7) -- Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.
Adult DoseOPC: 10-mg troche to be dissolved in mouth 5 times/d for 7 d
Cutaneous candidiasis: Apply 1% cream, lotion, or solution bid/tid
Vaginal candidiasis: 100-mg pessaries qd for 6 d; 1 applicatorful intravaginally of 1%, 2%, or 10% cream hs
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsNot for treatment of systemic fungal infections; avoid contact with the eyes; if irritation or sensitivity develops, discontinue use and institute appropriate therapy
Drug Name
Butoconazole (Femstat-3, Gynazole-1) -- Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.
Use 2% vaginal cream. Available OTC.
Adult DoseVaginal candidiasis: Insert 1 applicatorful (5 g) intravaginally hs for 3 d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsIf sensitivity or chemical irritation occurs, discontinue use; external use only; avoid contact with eyes
Drug Name
Miconazole (Monistat, Micatin) -- Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death. Lotion preferred in intertriginous areas. If cream is used, apply sparingly to avoid maceration effects.
Adult DoseVaginal candidiasis: Insert a single 200-mg suppository intravaginally hs for 3 d; alternatively, insert 1 applicatorful of 2% vaginal cream intravaginally hs for 7 d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsIf sensitivity or chemical irritation occurs, discontinue use; external use only; avoid contact with eyes
Drug Name
Tioconazole (Vagistat-1) -- Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death.
Adult DoseVaginal candidiasis: Insert 1 applicatorful intravaginally prior to hs
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsIf sensitivity or chemical irritation occurs, discontinue use; external use only; avoid contact with eyes
Drug Name
Terconazole (Terazol-7, Terazol-3) -- Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out, resulting in fungal cell death.
Adult DoseVaginal candidiasis
80-mg tab: Insert 1 suppository (2.5 g) intravaginally hs for 3 d
0.4% cream: Insert 1 applicatorful (5 g) intravaginally hs for 7 d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsIf sensitivity or chemical irritation occurs, discontinue use; use only externally; avoid contact with eyes
Drug Category: Glucan synthesis inhibitors (echinocandins) -- These agents inhibit formation of fungal cell wall. The first drug is caspofungin, approved by the FDA in 2001. The class has grown with the recent approval of micafungin and anidulafungin. Indications are evolving and will probably include complicated forms of invasive candidiasis, candidemia, disease refractory to other systemic antifungals, and intolerance to amphotericin B. They appear to be active against all Candida species
Drug Name
Caspofungin (Cancidas) -- FDA approved to treat candidemia, invasive candidiasis, and esophageal candidiasis. Initially approved to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.
Adult Dose70 mg IV over 1 h on day 1; 50 mg IV qd thereafter
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsCoadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels; may decrease levels of tacrolimus
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in moderate hepatic dysfunction (decrease dose); may exacerbate preexisting renal dysfunction or myelosuppression
Drug Name
Micafungin (Mycamine) -- Member of new class of antifungal agents, echinocandins, that inhibits cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells. Indications include prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and treatment of esophageal candidiasis.
Adult DoseCandidiasis prophylaxis stem cell transplant recipient: 50 mg IV qd infused over 1 h
Esophageal candidiasis: 150 mg IV qd infused over 1 h.
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsIncreases sirolimus and nifedipine AUC approximately 20%
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCommon adverse effects include headache, nausea, vomiting, and abdominal pain; other adverse effects include rash, delirium, phlebitis, shock, leukopenia, and hyperbilirubinemia; rare cases of elevated hepatic enzyme, BUN, and creatine levels reported; transient acute intravascular hemolysis and hemoglobinuria may occur; do not mix or infuse in same IV line with other medications because precipitate forms with other commonly used medications (flush existing IV line with 0.9% NaCl before and after infusion); protect from light following dilution
Drug Name
Anidulafungin (Eraxis) -- Antifungal agent of the echinocandin class. Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls. Indicated to treat esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intra-abdominal abscesses, peritonitis).
Adult DoseCandidemia or other candidal infections: 200 mg IV on day 1, decrease dose on day 2 and thereafter to 100 mg/d IV
Esophageal candidiasis: 100 mg IV on day 1, decrease dose on day 2 and thereafter to 50 mg/d IV
Do not exceed infusion rate of 1.1 mg/min
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCommon adverse effects include hypokalemia, diarrhea, elevated hepatic enzyme levels, and headache; rare reports of serious hepatotoxicity; infusion-related reactions (eg, rash, urticaria, flushing, pruritus, dyspnea, hypotension) may occur, particularly with rapid infusion; following reconstitution, dilute further with D5W or NS before administration

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