Mycetoma is a subcutaneous disease that can be caused by aerobic bacteria (actinomycetoma) or fungi (eumycetoma). Diagnosis is based on clinical manifestations, including swelling and deformity of affected areas, as well as the presence of granulation tissue, scars, abscesses, sinus tracts, and a purulent exudate that contains the microorganisms.

The worldwide proportion of mycetomas is 60% actinomycetomas and 40% eumycetomas.¹ The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela.¹

Although mycetoma is rare in developed countries, migration of patients from endemic areas makes knowledge of this condition crucial for dermatologists worldwide. We present a review of the current concepts in the epidemiology, clinical presentation, diagnosis, and treatment of actinomycetoma.

Epidemiology

Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico.² The majority of cases of mycetoma in Mexico are actinomycetoma (98%), including Nocardia (86%) and Actinomadura madurae (10%). Eumycetoma is rare in Mexico, constituting only 2% of cases.² Worldwide, men are affected more commonly than women, which is thought to be related to a higher occupational risk during agricultural labor.

Clinical Features

Mycetoma can affect the skin, subcutaneous tissue, bones, and occasionally the internal organs. It is characterized by swelling, deformation of the affected area, and fistulae that drain serosanguineous or purulent exudates.

In Mexico, 60% of cases of mycetoma affect the lower extremities; the feet are the most commonly affected area, followed by the trunk (back and chest), arms, forearms, legs, knees, and thighs.¹ Other sites include the hands, shoulders, and abdominal wall. The head and neck area are seldom affected.³ Mycetoma lesions grow and disseminate locally. Bone lesions are possible depending on the osteophilic affinity of the etiological agent and on the interactions between the fungus and the host’s immune system. In severe advanced cases of mycetoma, the lesions may involve tendons and nerves. Dissemination via blood or lymphatics is extremely rare.⁴

Diagnosis

Diagnosis of actinomycetoma is suspected based on clinical features and confirmed by direct examination of exudates with Lugol iodine or saline solution. On direct microscopy, actinomycetes are recognized by the production of filaments with a width of 0.5 to 1 μm. On hematoxylin and eosin stain, the small grains of Nocardia appear eosinophilic with a blue center and pink filaments. On Gram stain, actinomycetoma grains show positive branching filaments. Culture of grains recovered from aspirated material or biopsy specimens provides specific etiologic diagnosis. Cultures should be held for at least 4 weeks. Additionally, there are some enzymatic, molecular, and serologic tests available for diagnosis.^5-7 Serologic diagnosis is available in a few centers in Mexico and can be helpful in some cases for diagnosis or follow-up during treatment. Antibodies can be determined via enzyme-linked immunosorbent assay, Western blot analysis, immunodiffusion, or counterimmunoelectrophoresis.⁸

The causative agents of actinomycetoma can be isolated in Sabouraud dextrose agar. Deep wedge biopsies (or puncture aspiration) are useful in observing the diagnostic grains, which can be identified adequately with Gram stain. Grains usually are surrounded and/or infiltrated by neutrophils. The size, form, and color of grains can identify the causative agent.¹ The granules of Nocardia are small (80–130 mm) and reniform or wormlike, with club structures in their periphery (Figure 1). Actinomadura madurae is characterized by large, white-yellow granules that can be seen with the naked eye (1–3 mm). On microscopic examination with hematoxylin and eosin stain, these grains are purple and exhibit peripheral pink pseudofilaments (Figure 2).² The grains of Actinomadura pelletieri are large (1–3 mm) and red or violaceous. They fragment or break easily, giving the appearance of a broken dish (Figure 3). Streptomyces somaliensis forms round grains approximately 0.5 to 1 cm in diameter. These grains stain poorly and are extremely hard. Cutting the grains during processing results in striation, giving them the appearance of a potato chip (Figure 4).²

Treatment of Actinomycetoma

Precise identification of the etiologic agent is essential to provide effective treatment of actinomycetoma. Without treatment, or in resistant cases, progressive osseous and visceral involvement is inevitable.⁹ Actinomycetoma without osseous involvement usually responds well to medical treatment.

The treatment of choice for actinomycetoma involving Nocardia brasiliensis is a combination of dapsone 100 to 200 mg once daily and trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 to 160/800 mg once daily for 2 to 3 years.¹⁰ Other treatments have included the following: (1) amikacin 15 mg/kg or 500 mg intramuscularly twice daily for 3 weeks plus dapsone 100 to 200 mg once daily plus TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years (amikacin, however, is expensive and potentially toxic [nephrotoxicity and ototoxicity] and therefore is used only in resistant cases); (2) dapsone 100 to 200 mg once daily or TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years plus intramuscular kanamycin 15 mg/kg once daily for 2 weeks at the beginning of treatment, alternating with rest periods to reduce the risk for nephrotoxicity and ototoxicity¹⁰; (3) dapsone 1.5 mg/kg orally twice daily plus phosphomycin 500 mg once daily; (4) dapsone 1.5 mg/kg orally twice daily plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month, then the same dose every other day for 1 to 2 months monitoring for ototoxicity; and (5) TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years or rifampicin (15–20 mg/kg/d) plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month at the beginning of treatment, then the same dose every other day for 2 to 3 months until a total dose of 60 g is administered, monitoring for ototoxicity.¹¹ Audiometric tests and creatinine levels must be performed every 5 weeks during the treatment to monitor toxicity.¹⁰

The best results for infections with A pelletieri, A madurae, and S somaliensis have been with streptomycin (1 g once daily in adults; 20 mg/kg once daily in children) until a total dose of 50 g is reached in combination with TMP-SMX or dapsone¹² (Figure 5). Alternatives for A madurae infections include streptomycin plus oral clofazimine (100 mg once daily), oral rifampicin (300 mg twice daily), oral tetracycline (1 g once daily), oral isoniazid (300–600 mg once daily), or oral minocycline (100 mg twice daily; also effective for A pelletieri).

More recently, other drugs have been used such as carbapenems (eg, imipenem, meropenem), which have wide-spectrum efficacy and are resistant to β-lactamases. Patients should be hospitalized to receive intravenous therapy with imipenem.² Carbapenems are effective against gram-positive and gram-negative as well as Nocardia species.^13,14 Mycetoma that is resistant, severe, or has visceral involvement can be treated with a combination of amikacin and imipenem.^15,16 Meropenem is a similar drug that is available as an oral formulation. Both imipenem and meropenem are recommended in cases with bone involvement.^17,18 Alternatives for resistant cases include amoxicillin–clavulanic acid 500/125 mg orally 3 times daily for 3 to 6 months or intravenous cefotaxime 1 g every 8 hours plus intramuscular amikacin 500 mg twice daily plus oral levamisole 300 mg once weekly for 4 weeks.^19-23

For resistant cases associated with Nocardia species, clindamycin plus quinolones (eg, ciprofloxacin, moxifloxacin, garenoxacin) at a dose of 25 mg/kg once daily for at least 3 months has been suggested in in vivo studies.²³

Overall, the cure rate for actinomycetoma treated with any of the prior therapies ranges from 60% to 90%. Treatment must be modified or stopped if there is clinical or laboratory evidence of drug toxicity.^13,24 Surgical treatment of actinomycetoma is contraindicated, as it may cause hematogenous dissemination.

Prognosis

Actinomycetomas of a few months’ duration and without bone involvement respond well to therapy. If no therapy is provided or if there is resistance, the functional and cosmetic prognosis is poor, mainly for the feet. There is a risk for spine involvement with mycetoma on the back and posterior head. Thoracic lesions may penetrate into the lungs. The muscular fascia impedes the penetration of abdominal lesions, but the inguinal canals can offer a path for intra-abdominal dissemination.⁴ Advanced cases lead to a poor general condition of patients, difficulty in using affected extremities, and in extreme cases even death.

The criteria used to guide the discontinuation of initial therapy for any mycetoma include a decrease in the volume of the lesion, closure of fistulae, 3 consecutive negative monthly cultures, imaging studies showing bone regeneration, lack of echoes and cavities on echography, and absence of grains on examination of fine-needle aspirates.¹¹ After the initial treatment protocol is finished, most experts recommend continuing treatment with dapsone 100 to 300 mg once daily for several years to prevent recurrence.¹²

Prevention

Mycetoma is a disease associated with poverty. It could be prevented by improving living conditions and by regular use of shoes in rural populations.²

Conclusion

Mycetoma is a chronic infection that develops after traumatic inoculation of the skin with either true fungi or aerobic actinomycetes. The resultant infections are known as eumycetoma or actinomycetoma, respectively. The etiologic agents can be found in the so-called grains. Black grains suggest a fungal infection, minute white grains suggest Nocardia, and red grains are due to A pelletieri. Larger white grains or yellow-white grains may be fungal or actinomycotic in origin.

Specific diagnosis requires direct examination, culture, and biopsy. The treatment of choice for actinomycetoma by N brasiliensis is a combination of dapsone 100 to 200 mg once daily and TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years. Other effective treatments include aminoglycosides (eg, amikacine, streptomycin) and quinolones. More recently, some other agents have been used such as carbapenems and natural products of Streptomyces cattleya (imipenem), which have wide-spectrum efficacy and are resistant to β-lactamases.

Mycetoma is a subcutaneous disease that can be caused by aerobic bacteria (actinomycetoma) or fungi (eumycetoma). Diagnosis is based on clinical manifestations, including swelling and deformity of affected areas, as well as the presence of granulation tissue, scars, abscesses, sinus tracts, and a purulent exudate that contains the microorganisms.

The worldwide proportion of mycetomas is 60% actinomycetomas and 40% eumycetomas.¹ The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela.¹

Although mycetoma is rare in developed countries, migration of patients from endemic areas makes knowledge of this condition crucial for dermatologists worldwide. We present a review of the current concepts in the epidemiology, clinical presentation, diagnosis, and treatment of actinomycetoma.

Epidemiology

Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico.² The majority of cases of mycetoma in Mexico are actinomycetoma (98%), including Nocardia (86%) and Actinomadura madurae (10%). Eumycetoma is rare in Mexico, constituting only 2% of cases.² Worldwide, men are affected more commonly than women, which is thought to be related to a higher occupational risk during agricultural labor.

Clinical Features

Mycetoma can affect the skin, subcutaneous tissue, bones, and occasionally the internal organs. It is characterized by swelling, deformation of the affected area, and fistulae that drain serosanguineous or purulent exudates.

In Mexico, 60% of cases of mycetoma affect the lower extremities; the feet are the most commonly affected area, followed by the trunk (back and chest), arms, forearms, legs, knees, and thighs.¹ Other sites include the hands, shoulders, and abdominal wall. The head and neck area are seldom affected.³ Mycetoma lesions grow and disseminate locally. Bone lesions are possible depending on the osteophilic affinity of the etiological agent and on the interactions between the fungus and the host’s immune system. In severe advanced cases of mycetoma, the lesions may involve tendons and nerves. Dissemination via blood or lymphatics is extremely rare.⁴

Diagnosis

Diagnosis of actinomycetoma is suspected based on clinical features and confirmed by direct examination of exudates with Lugol iodine or saline solution. On direct microscopy, actinomycetes are recognized by the production of filaments with a width of 0.5 to 1 μm. On hematoxylin and eosin stain, the small grains of Nocardia appear eosinophilic with a blue center and pink filaments. On Gram stain, actinomycetoma grains show positive branching filaments. Culture of grains recovered from aspirated material or biopsy specimens provides specific etiologic diagnosis. Cultures should be held for at least 4 weeks. Additionally, there are some enzymatic, molecular, and serologic tests available for diagnosis.^5-7 Serologic diagnosis is available in a few centers in Mexico and can be helpful in some cases for diagnosis or follow-up during treatment. Antibodies can be determined via enzyme-linked immunosorbent assay, Western blot analysis, immunodiffusion, or counterimmunoelectrophoresis.⁸

The causative agents of actinomycetoma can be isolated in Sabouraud dextrose agar. Deep wedge biopsies (or puncture aspiration) are useful in observing the diagnostic grains, which can be identified adequately with Gram stain. Grains usually are surrounded and/or infiltrated by neutrophils. The size, form, and color of grains can identify the causative agent.¹ The granules of Nocardia are small (80–130 mm) and reniform or wormlike, with club structures in their periphery (Figure 1). Actinomadura madurae is characterized by large, white-yellow granules that can be seen with the naked eye (1–3 mm). On microscopic examination with hematoxylin and eosin stain, these grains are purple and exhibit peripheral pink pseudofilaments (Figure 2).² The grains of Actinomadura pelletieri are large (1–3 mm) and red or violaceous. They fragment or break easily, giving the appearance of a broken dish (Figure 3). Streptomyces somaliensis forms round grains approximately 0.5 to 1 cm in diameter. These grains stain poorly and are extremely hard. Cutting the grains during processing results in striation, giving them the appearance of a potato chip (Figure 4).²

Treatment of Actinomycetoma

Precise identification of the etiologic agent is essential to provide effective treatment of actinomycetoma. Without treatment, or in resistant cases, progressive osseous and visceral involvement is inevitable.⁹ Actinomycetoma without osseous involvement usually responds well to medical treatment.

The treatment of choice for actinomycetoma involving Nocardia brasiliensis is a combination of dapsone 100 to 200 mg once daily and trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 to 160/800 mg once daily for 2 to 3 years.¹⁰ Other treatments have included the following: (1) amikacin 15 mg/kg or 500 mg intramuscularly twice daily for 3 weeks plus dapsone 100 to 200 mg once daily plus TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years (amikacin, however, is expensive and potentially toxic [nephrotoxicity and ototoxicity] and therefore is used only in resistant cases); (2) dapsone 100 to 200 mg once daily or TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years plus intramuscular kanamycin 15 mg/kg once daily for 2 weeks at the beginning of treatment, alternating with rest periods to reduce the risk for nephrotoxicity and ototoxicity¹⁰; (3) dapsone 1.5 mg/kg orally twice daily plus phosphomycin 500 mg once daily; (4) dapsone 1.5 mg/kg orally twice daily plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month, then the same dose every other day for 1 to 2 months monitoring for ototoxicity; and (5) TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years or rifampicin (15–20 mg/kg/d) plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month at the beginning of treatment, then the same dose every other day for 2 to 3 months until a total dose of 60 g is administered, monitoring for ototoxicity.¹¹ Audiometric tests and creatinine levels must be performed every 5 weeks during the treatment to monitor toxicity.¹⁰

The best results for infections with A pelletieri, A madurae, and S somaliensis have been with streptomycin (1 g once daily in adults; 20 mg/kg once daily in children) until a total dose of 50 g is reached in combination with TMP-SMX or dapsone¹² (Figure 5). Alternatives for A madurae infections include streptomycin plus oral clofazimine (100 mg once daily), oral rifampicin (300 mg twice daily), oral tetracycline (1 g once daily), oral isoniazid (300–600 mg once daily), or oral minocycline (100 mg twice daily; also effective for A pelletieri).

More recently, other drugs have been used such as carbapenems (eg, imipenem, meropenem), which have wide-spectrum efficacy and are resistant to β-lactamases. Patients should be hospitalized to receive intravenous therapy with imipenem.² Carbapenems are effective against gram-positive and gram-negative as well as Nocardia species.^13,14 Mycetoma that is resistant, severe, or has visceral involvement can be treated with a combination of amikacin and imipenem.^15,16 Meropenem is a similar drug that is available as an oral formulation. Both imipenem and meropenem are recommended in cases with bone involvement.^17,18 Alternatives for resistant cases include amoxicillin–clavulanic acid 500/125 mg orally 3 times daily for 3 to 6 months or intravenous cefotaxime 1 g every 8 hours plus intramuscular amikacin 500 mg twice daily plus oral levamisole 300 mg once weekly for 4 weeks.^19-23

For resistant cases associated with Nocardia species, clindamycin plus quinolones (eg, ciprofloxacin, moxifloxacin, garenoxacin) at a dose of 25 mg/kg once daily for at least 3 months has been suggested in in vivo studies.²³

Overall, the cure rate for actinomycetoma treated with any of the prior therapies ranges from 60% to 90%. Treatment must be modified or stopped if there is clinical or laboratory evidence of drug toxicity.^13,24 Surgical treatment of actinomycetoma is contraindicated, as it may cause hematogenous dissemination.

Prognosis

Actinomycetomas of a few months’ duration and without bone involvement respond well to therapy. If no therapy is provided or if there is resistance, the functional and cosmetic prognosis is poor, mainly for the feet. There is a risk for spine involvement with mycetoma on the back and posterior head. Thoracic lesions may penetrate into the lungs. The muscular fascia impedes the penetration of abdominal lesions, but the inguinal canals can offer a path for intra-abdominal dissemination.⁴ Advanced cases lead to a poor general condition of patients, difficulty in using affected extremities, and in extreme cases even death.

The criteria used to guide the discontinuation of initial therapy for any mycetoma include a decrease in the volume of the lesion, closure of fistulae, 3 consecutive negative monthly cultures, imaging studies showing bone regeneration, lack of echoes and cavities on echography, and absence of grains on examination of fine-needle aspirates.¹¹ After the initial treatment protocol is finished, most experts recommend continuing treatment with dapsone 100 to 300 mg once daily for several years to prevent recurrence.¹²

Prevention

Mycetoma is a disease associated with poverty. It could be prevented by improving living conditions and by regular use of shoes in rural populations.²

Conclusion

Mycetoma is a chronic infection that develops after traumatic inoculation of the skin with either true fungi or aerobic actinomycetes. The resultant infections are known as eumycetoma or actinomycetoma, respectively. The etiologic agents can be found in the so-called grains. Black grains suggest a fungal infection, minute white grains suggest Nocardia, and red grains are due to A pelletieri. Larger white grains or yellow-white grains may be fungal or actinomycotic in origin.

Specific diagnosis requires direct examination, culture, and biopsy. The treatment of choice for actinomycetoma by N brasiliensis is a combination of dapsone 100 to 200 mg once daily and TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years. Other effective treatments include aminoglycosides (eg, amikacine, streptomycin) and quinolones. More recently, some other agents have been used such as carbapenems and natural products of Streptomyces cattleya (imipenem), which have wide-spectrum efficacy and are resistant to β-lactamases.

Mycetoma is a subcutaneous disease that can be caused by aerobic bacteria (actinomycetoma) or fungi (eumycetoma). Diagnosis is based on clinical manifestations, including swelling and deformity of affected areas, as well as the presence of granulation tissue, scars, abscesses, sinus tracts, and a purulent exudate that contains the microorganisms.

The worldwide proportion of mycetomas is 60% actinomycetomas and 40% eumycetomas.¹ The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela.¹

Although mycetoma is rare in developed countries, migration of patients from endemic areas makes knowledge of this condition crucial for dermatologists worldwide. We present a review of the current concepts in the epidemiology, clinical presentation, diagnosis, and treatment of actinomycetoma.

Epidemiology

Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico.² The majority of cases of mycetoma in Mexico are actinomycetoma (98%), including Nocardia (86%) and Actinomadura madurae (10%). Eumycetoma is rare in Mexico, constituting only 2% of cases.² Worldwide, men are affected more commonly than women, which is thought to be related to a higher occupational risk during agricultural labor.

Clinical Features

Mycetoma can affect the skin, subcutaneous tissue, bones, and occasionally the internal organs. It is characterized by swelling, deformation of the affected area, and fistulae that drain serosanguineous or purulent exudates.

In Mexico, 60% of cases of mycetoma affect the lower extremities; the feet are the most commonly affected area, followed by the trunk (back and chest), arms, forearms, legs, knees, and thighs.¹ Other sites include the hands, shoulders, and abdominal wall. The head and neck area are seldom affected.³ Mycetoma lesions grow and disseminate locally. Bone lesions are possible depending on the osteophilic affinity of the etiological agent and on the interactions between the fungus and the host’s immune system. In severe advanced cases of mycetoma, the lesions may involve tendons and nerves. Dissemination via blood or lymphatics is extremely rare.⁴

Diagnosis

Diagnosis of actinomycetoma is suspected based on clinical features and confirmed by direct examination of exudates with Lugol iodine or saline solution. On direct microscopy, actinomycetes are recognized by the production of filaments with a width of 0.5 to 1 μm. On hematoxylin and eosin stain, the small grains of Nocardia appear eosinophilic with a blue center and pink filaments. On Gram stain, actinomycetoma grains show positive branching filaments. Culture of grains recovered from aspirated material or biopsy specimens provides specific etiologic diagnosis. Cultures should be held for at least 4 weeks. Additionally, there are some enzymatic, molecular, and serologic tests available for diagnosis.^5-7 Serologic diagnosis is available in a few centers in Mexico and can be helpful in some cases for diagnosis or follow-up during treatment. Antibodies can be determined via enzyme-linked immunosorbent assay, Western blot analysis, immunodiffusion, or counterimmunoelectrophoresis.⁸

The causative agents of actinomycetoma can be isolated in Sabouraud dextrose agar. Deep wedge biopsies (or puncture aspiration) are useful in observing the diagnostic grains, which can be identified adequately with Gram stain. Grains usually are surrounded and/or infiltrated by neutrophils. The size, form, and color of grains can identify the causative agent.¹ The granules of Nocardia are small (80–130 mm) and reniform or wormlike, with club structures in their periphery (Figure 1). Actinomadura madurae is characterized by large, white-yellow granules that can be seen with the naked eye (1–3 mm). On microscopic examination with hematoxylin and eosin stain, these grains are purple and exhibit peripheral pink pseudofilaments (Figure 2).² The grains of Actinomadura pelletieri are large (1–3 mm) and red or violaceous. They fragment or break easily, giving the appearance of a broken dish (Figure 3). Streptomyces somaliensis forms round grains approximately 0.5 to 1 cm in diameter. These grains stain poorly and are extremely hard. Cutting the grains during processing results in striation, giving them the appearance of a potato chip (Figure 4).²

Treatment of Actinomycetoma

Precise identification of the etiologic agent is essential to provide effective treatment of actinomycetoma. Without treatment, or in resistant cases, progressive osseous and visceral involvement is inevitable.⁹ Actinomycetoma without osseous involvement usually responds well to medical treatment.

The treatment of choice for actinomycetoma involving Nocardia brasiliensis is a combination of dapsone 100 to 200 mg once daily and trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 to 160/800 mg once daily for 2 to 3 years.¹⁰ Other treatments have included the following: (1) amikacin 15 mg/kg or 500 mg intramuscularly twice daily for 3 weeks plus dapsone 100 to 200 mg once daily plus TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years (amikacin, however, is expensive and potentially toxic [nephrotoxicity and ototoxicity] and therefore is used only in resistant cases); (2) dapsone 100 to 200 mg once daily or TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years plus intramuscular kanamycin 15 mg/kg once daily for 2 weeks at the beginning of treatment, alternating with rest periods to reduce the risk for nephrotoxicity and ototoxicity¹⁰; (3) dapsone 1.5 mg/kg orally twice daily plus phosphomycin 500 mg once daily; (4) dapsone 1.5 mg/kg orally twice daily plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month, then the same dose every other day for 1 to 2 months monitoring for ototoxicity; and (5) TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years or rifampicin (15–20 mg/kg/d) plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month at the beginning of treatment, then the same dose every other day for 2 to 3 months until a total dose of 60 g is administered, monitoring for ototoxicity.¹¹ Audiometric tests and creatinine levels must be performed every 5 weeks during the treatment to monitor toxicity.¹⁰

The best results for infections with A pelletieri, A madurae, and S somaliensis have been with streptomycin (1 g once daily in adults; 20 mg/kg once daily in children) until a total dose of 50 g is reached in combination with TMP-SMX or dapsone¹² (Figure 5). Alternatives for A madurae infections include streptomycin plus oral clofazimine (100 mg once daily), oral rifampicin (300 mg twice daily), oral tetracycline (1 g once daily), oral isoniazid (300–600 mg once daily), or oral minocycline (100 mg twice daily; also effective for A pelletieri).

More recently, other drugs have been used such as carbapenems (eg, imipenem, meropenem), which have wide-spectrum efficacy and are resistant to β-lactamases. Patients should be hospitalized to receive intravenous therapy with imipenem.² Carbapenems are effective against gram-positive and gram-negative as well as Nocardia species.^13,14 Mycetoma that is resistant, severe, or has visceral involvement can be treated with a combination of amikacin and imipenem.^15,16 Meropenem is a similar drug that is available as an oral formulation. Both imipenem and meropenem are recommended in cases with bone involvement.^17,18 Alternatives for resistant cases include amoxicillin–clavulanic acid 500/125 mg orally 3 times daily for 3 to 6 months or intravenous cefotaxime 1 g every 8 hours plus intramuscular amikacin 500 mg twice daily plus oral levamisole 300 mg once weekly for 4 weeks.^19-23

For resistant cases associated with Nocardia species, clindamycin plus quinolones (eg, ciprofloxacin, moxifloxacin, garenoxacin) at a dose of 25 mg/kg once daily for at least 3 months has been suggested in in vivo studies.²³

Overall, the cure rate for actinomycetoma treated with any of the prior therapies ranges from 60% to 90%. Treatment must be modified or stopped if there is clinical or laboratory evidence of drug toxicity.^13,24 Surgical treatment of actinomycetoma is contraindicated, as it may cause hematogenous dissemination.

Prognosis

Actinomycetomas of a few months’ duration and without bone involvement respond well to therapy. If no therapy is provided or if there is resistance, the functional and cosmetic prognosis is poor, mainly for the feet. There is a risk for spine involvement with mycetoma on the back and posterior head. Thoracic lesions may penetrate into the lungs. The muscular fascia impedes the penetration of abdominal lesions, but the inguinal canals can offer a path for intra-abdominal dissemination.⁴ Advanced cases lead to a poor general condition of patients, difficulty in using affected extremities, and in extreme cases even death.

The criteria used to guide the discontinuation of initial therapy for any mycetoma include a decrease in the volume of the lesion, closure of fistulae, 3 consecutive negative monthly cultures, imaging studies showing bone regeneration, lack of echoes and cavities on echography, and absence of grains on examination of fine-needle aspirates.¹¹ After the initial treatment protocol is finished, most experts recommend continuing treatment with dapsone 100 to 300 mg once daily for several years to prevent recurrence.¹²

Prevention

Mycetoma is a disease associated with poverty. It could be prevented by improving living conditions and by regular use of shoes in rural populations.²

Conclusion

Mycetoma is a chronic infection that develops after traumatic inoculation of the skin with either true fungi or aerobic actinomycetes. The resultant infections are known as eumycetoma or actinomycetoma, respectively. The etiologic agents can be found in the so-called grains. Black grains suggest a fungal infection, minute white grains suggest Nocardia, and red grains are due to A pelletieri. Larger white grains or yellow-white grains may be fungal or actinomycotic in origin.

Specific diagnosis requires direct examination, culture, and biopsy. The treatment of choice for actinomycetoma by N brasiliensis is a combination of dapsone 100 to 200 mg once daily and TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years. Other effective treatments include aminoglycosides (eg, amikacine, streptomycin) and quinolones. More recently, some other agents have been used such as carbapenems and natural products of Streptomyces cattleya (imipenem), which have wide-spectrum efficacy and are resistant to β-lactamases.

Updated lipid management guidelines include a category of “extreme risk” patients in whom LDL cholesterol should be lowered below 55 mg/dL, according to a summary by the American Association of Clinical Endocrinologists and American College of Endocrinology.

Achieving such a low LDL-cholesterol (LDL-C) level is possible with well-established medications such as a combination of simvastatin and ezetimibe and the newer, more clinically powerful agent PCSK9 inhibitors, Paul S. Jellinger, MD, chair of the guideline committee and professor of clinical medicine, University of Miami, said in an interview. The “extreme risk” category was derived largely from IMPROVE-IT and supporting meta-analyses.

Heterozygous hypercholesterolemia is more common than many physicians realize, affecting as it does 1 in 250 people, Dr. Jellinger noted.

“Supporting evidence for the ‘extreme risk’ category with an LDL-C of less than 55 mg/dL was recently announced with the top line results from the FOURIER CVD outcome trial utilizing PCSK9-inhibitor therapy, which met both its primary and secondary endpoints,” he stressed.

PCSK9 inhibitors are extremely expensive, said Dr. Jellinger. “In my view, payers should not be denying patients who clearly meet the Food and Drug Administration approved indications for PCSK9 inhibitors and those within the extreme risk criteria. Yet, I have been made aware that 80% of insurance claims for PCSK9 inhibitors in these extremely high-risk and vulnerable patients are being denied.”

Inclusion in the updated AACE lipid management guidelines should strengthen PCSK9 inhibitors’ place among lipid-lowering drugs that are acceptable to insurance companies by making it clear that PCSK9 is appropriate and indicated for select patients, according to Dr. Jellinger.

Aside from creation of the extreme risk category, the AACE lipid guidelines discuss the available tools for making a global risk assessment of having a cardiac, vascular, or stroke event in the next 10 years, without favoring any one risk score. Among the systems discussed, with links, are the Framingham, MESA (Multi-Ethnic Study of Atherosclerosis), Reynolds, and United Kingdom Prospective Diabetes Study risk scores.

The guidelines provide separate approaches to management of people at various ages. Another change from the 2012 guidelines is the establishment of acceptable and worrisome LDL-C levels in children: Acceptable is a level under 100 mg/dL, borderline is 100-129 mg/dL, and high is LDL-C at or above 130 mg/dL.

The guidelines, which will be published in full in the April issue of Endocrine Practice, are based largely on numerous clinical trials and studies, and in the end produced 87 recommendations, of which 45 are Grade A, 18 are Grade B, 15 are Grade C, and 9 are Grade D.

These are the first guidelines on lipid management from AACE since 2012. The executive summary of the guidelines is available at www.aace.com.

Dr. Jellinger reported receiving speakers honoraria from Amgen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk.
 

[email protected]

Updated lipid management guidelines include a category of “extreme risk” patients in whom LDL cholesterol should be lowered below 55 mg/dL, according to a summary by the American Association of Clinical Endocrinologists and American College of Endocrinology.

Achieving such a low LDL-cholesterol (LDL-C) level is possible with well-established medications such as a combination of simvastatin and ezetimibe and the newer, more clinically powerful agent PCSK9 inhibitors, Paul S. Jellinger, MD, chair of the guideline committee and professor of clinical medicine, University of Miami, said in an interview. The “extreme risk” category was derived largely from IMPROVE-IT and supporting meta-analyses.

Heterozygous hypercholesterolemia is more common than many physicians realize, affecting as it does 1 in 250 people, Dr. Jellinger noted.

“Supporting evidence for the ‘extreme risk’ category with an LDL-C of less than 55 mg/dL was recently announced with the top line results from the FOURIER CVD outcome trial utilizing PCSK9-inhibitor therapy, which met both its primary and secondary endpoints,” he stressed.

PCSK9 inhibitors are extremely expensive, said Dr. Jellinger. “In my view, payers should not be denying patients who clearly meet the Food and Drug Administration approved indications for PCSK9 inhibitors and those within the extreme risk criteria. Yet, I have been made aware that 80% of insurance claims for PCSK9 inhibitors in these extremely high-risk and vulnerable patients are being denied.”

Inclusion in the updated AACE lipid management guidelines should strengthen PCSK9 inhibitors’ place among lipid-lowering drugs that are acceptable to insurance companies by making it clear that PCSK9 is appropriate and indicated for select patients, according to Dr. Jellinger.

Aside from creation of the extreme risk category, the AACE lipid guidelines discuss the available tools for making a global risk assessment of having a cardiac, vascular, or stroke event in the next 10 years, without favoring any one risk score. Among the systems discussed, with links, are the Framingham, MESA (Multi-Ethnic Study of Atherosclerosis), Reynolds, and United Kingdom Prospective Diabetes Study risk scores.

The guidelines provide separate approaches to management of people at various ages. Another change from the 2012 guidelines is the establishment of acceptable and worrisome LDL-C levels in children: Acceptable is a level under 100 mg/dL, borderline is 100-129 mg/dL, and high is LDL-C at or above 130 mg/dL.

The guidelines, which will be published in full in the April issue of Endocrine Practice, are based largely on numerous clinical trials and studies, and in the end produced 87 recommendations, of which 45 are Grade A, 18 are Grade B, 15 are Grade C, and 9 are Grade D.

These are the first guidelines on lipid management from AACE since 2012. The executive summary of the guidelines is available at www.aace.com.

Dr. Jellinger reported receiving speakers honoraria from Amgen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk.
 

[email protected]

Updated lipid management guidelines include a category of “extreme risk” patients in whom LDL cholesterol should be lowered below 55 mg/dL, according to a summary by the American Association of Clinical Endocrinologists and American College of Endocrinology.

Achieving such a low LDL-cholesterol (LDL-C) level is possible with well-established medications such as a combination of simvastatin and ezetimibe and the newer, more clinically powerful agent PCSK9 inhibitors, Paul S. Jellinger, MD, chair of the guideline committee and professor of clinical medicine, University of Miami, said in an interview. The “extreme risk” category was derived largely from IMPROVE-IT and supporting meta-analyses.

Heterozygous hypercholesterolemia is more common than many physicians realize, affecting as it does 1 in 250 people, Dr. Jellinger noted.

“Supporting evidence for the ‘extreme risk’ category with an LDL-C of less than 55 mg/dL was recently announced with the top line results from the FOURIER CVD outcome trial utilizing PCSK9-inhibitor therapy, which met both its primary and secondary endpoints,” he stressed.

PCSK9 inhibitors are extremely expensive, said Dr. Jellinger. “In my view, payers should not be denying patients who clearly meet the Food and Drug Administration approved indications for PCSK9 inhibitors and those within the extreme risk criteria. Yet, I have been made aware that 80% of insurance claims for PCSK9 inhibitors in these extremely high-risk and vulnerable patients are being denied.”

Inclusion in the updated AACE lipid management guidelines should strengthen PCSK9 inhibitors’ place among lipid-lowering drugs that are acceptable to insurance companies by making it clear that PCSK9 is appropriate and indicated for select patients, according to Dr. Jellinger.

Aside from creation of the extreme risk category, the AACE lipid guidelines discuss the available tools for making a global risk assessment of having a cardiac, vascular, or stroke event in the next 10 years, without favoring any one risk score. Among the systems discussed, with links, are the Framingham, MESA (Multi-Ethnic Study of Atherosclerosis), Reynolds, and United Kingdom Prospective Diabetes Study risk scores.

The guidelines provide separate approaches to management of people at various ages. Another change from the 2012 guidelines is the establishment of acceptable and worrisome LDL-C levels in children: Acceptable is a level under 100 mg/dL, borderline is 100-129 mg/dL, and high is LDL-C at or above 130 mg/dL.

The guidelines, which will be published in full in the April issue of Endocrine Practice, are based largely on numerous clinical trials and studies, and in the end produced 87 recommendations, of which 45 are Grade A, 18 are Grade B, 15 are Grade C, and 9 are Grade D.

These are the first guidelines on lipid management from AACE since 2012. The executive summary of the guidelines is available at www.aace.com.

Dr. Jellinger reported receiving speakers honoraria from Amgen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk.
 

[email protected]

High adherence to bronchiolitis clinical pathway recommendations in health care settings is associated with shorter length of stay (LOS) and lower health care costs, according to Mersine A. Bryan, MD, of the University of Washington, Seattle and her associates.

In a retrospective cohort study, researchers looked at 267 patients less than 24 months old diagnosed with bronchiolitis from December 2009 to July 2012. Levels of adherence were then categorized into low, middle, and high tertiles. Results show that adherence was highest for the inpatient quality indicators (mean score, 95) and lowest for the emergency department (ED) quality indicators (mean score, 79). The mean ED LOS was significantly shorter for cases with ED adherence scores in the highest versus the lowest tertile (90 vs. 140 minutes; P less than .05). There were no significant differences in mean inpatient LOS by inpatient adherence score tertiles. “However, the mean inpatient LOS was approximately 17 hours shorter for cases with combined ED/inpatient adherence scores in the highest, compared with the lowest tertile,” they said.

peterspiro/Thinkstock

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High adherence to bronchiolitis clinical pathway recommendations in health care settings is associated with shorter length of stay (LOS) and lower health care costs, according to Mersine A. Bryan, MD, of the University of Washington, Seattle and her associates.

In a retrospective cohort study, researchers looked at 267 patients less than 24 months old diagnosed with bronchiolitis from December 2009 to July 2012. Levels of adherence were then categorized into low, middle, and high tertiles. Results show that adherence was highest for the inpatient quality indicators (mean score, 95) and lowest for the emergency department (ED) quality indicators (mean score, 79). The mean ED LOS was significantly shorter for cases with ED adherence scores in the highest versus the lowest tertile (90 vs. 140 minutes; P less than .05). There were no significant differences in mean inpatient LOS by inpatient adherence score tertiles. “However, the mean inpatient LOS was approximately 17 hours shorter for cases with combined ED/inpatient adherence scores in the highest, compared with the lowest tertile,” they said.

peterspiro/Thinkstock

[email protected]

High adherence to bronchiolitis clinical pathway recommendations in health care settings is associated with shorter length of stay (LOS) and lower health care costs, according to Mersine A. Bryan, MD, of the University of Washington, Seattle and her associates.

In a retrospective cohort study, researchers looked at 267 patients less than 24 months old diagnosed with bronchiolitis from December 2009 to July 2012. Levels of adherence were then categorized into low, middle, and high tertiles. Results show that adherence was highest for the inpatient quality indicators (mean score, 95) and lowest for the emergency department (ED) quality indicators (mean score, 79). The mean ED LOS was significantly shorter for cases with ED adherence scores in the highest versus the lowest tertile (90 vs. 140 minutes; P less than .05). There were no significant differences in mean inpatient LOS by inpatient adherence score tertiles. “However, the mean inpatient LOS was approximately 17 hours shorter for cases with combined ED/inpatient adherence scores in the highest, compared with the lowest tertile,” they said.

peterspiro/Thinkstock

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SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.

Bruce Jancin/Frontline Medical News

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SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.

Bruce Jancin/Frontline Medical News

[email protected]

SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.

Bruce Jancin/Frontline Medical News

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The use of fecal microbiota transplantation is an option to eradicate highly drug-resistant enteric bacteria carriage, according to results from a small pilot study conducted by French investigators.

“A rapid and dramatic emergence of highly drug-resistant enteric bacteria (HDREB), i.e., carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant enterococci (VRE), is occurring worldwide,” researchers led by Benjamin Davido, MD, of the infectious diseases unit at Raymond Poincaré Teaching Hospital, Garches, France, wrote in a study published online Feb. 1 in the Journal of Hospital Infection. “Patients carrying these bacteria are at risk of developing severe infections due to these bacteria; these infections are associated with a high mortality rate, partially because of inappropriate antimicrobial treatment.”

copyright CDC/James Archer

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The use of fecal microbiota transplantation is an option to eradicate highly drug-resistant enteric bacteria carriage, according to results from a small pilot study conducted by French investigators.

“A rapid and dramatic emergence of highly drug-resistant enteric bacteria (HDREB), i.e., carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant enterococci (VRE), is occurring worldwide,” researchers led by Benjamin Davido, MD, of the infectious diseases unit at Raymond Poincaré Teaching Hospital, Garches, France, wrote in a study published online Feb. 1 in the Journal of Hospital Infection. “Patients carrying these bacteria are at risk of developing severe infections due to these bacteria; these infections are associated with a high mortality rate, partially because of inappropriate antimicrobial treatment.”

copyright CDC/James Archer

[email protected]

The use of fecal microbiota transplantation is an option to eradicate highly drug-resistant enteric bacteria carriage, according to results from a small pilot study conducted by French investigators.

“A rapid and dramatic emergence of highly drug-resistant enteric bacteria (HDREB), i.e., carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant enterococci (VRE), is occurring worldwide,” researchers led by Benjamin Davido, MD, of the infectious diseases unit at Raymond Poincaré Teaching Hospital, Garches, France, wrote in a study published online Feb. 1 in the Journal of Hospital Infection. “Patients carrying these bacteria are at risk of developing severe infections due to these bacteria; these infections are associated with a high mortality rate, partially because of inappropriate antimicrobial treatment.”

copyright CDC/James Archer

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Carriers of a hemochromatosis (HFE) gene mutation or a long (GT)n-repeat length within the HMOX1 promoter regions did not appear to have an increase in hemophilic arthropathy.

In 201 blood samples from patients with severe hemophilia A or B and 37 from patients with moderate disease, neither the presence of an HFE mutation nor a long (GT)n-repeat length was associated with an increase in joint damage. The assessment was based on Pettersson score after adjustment for disease severity, presence of inhibitors, annual joint bleeding rate (AJBR), age at Pettersson score and at clinic entrance, and birth cohort (standardized beta = 0.033 and -0.022, respectively), Lize F. van Vulpen, MD, of University Medical Center Utrecht, the Netherlands, reported at the annual meeting of the European Association of Haemophilia and Allied Disorders.

Study subjects had a median age of 43 years, median AJBRs of 2.5 and 0.5 for severe and moderate disease, respectively, and median Pettersson scores of 22 and 4 in the groups, respectively. An HFE mutation was detected in 91 patients, and their levels of ferritin, iron, and transferrin saturation were significantly increased, but other baseline characteristic were similar in those with and without HFE mutation, and regardless of (GT)n-repeat length.

The marked heterogeneity in joint damage seen among hemophilia patients was hypothesized in this study to be associated with differences in iron handling, but the findings failed to support that hypothesis, Dr. van Vulpen concluded.

Dr. van Vulpen reported having no disclosures.

[email protected]

Carriers of a hemochromatosis (HFE) gene mutation or a long (GT)n-repeat length within the HMOX1 promoter regions did not appear to have an increase in hemophilic arthropathy.

In 201 blood samples from patients with severe hemophilia A or B and 37 from patients with moderate disease, neither the presence of an HFE mutation nor a long (GT)n-repeat length was associated with an increase in joint damage. The assessment was based on Pettersson score after adjustment for disease severity, presence of inhibitors, annual joint bleeding rate (AJBR), age at Pettersson score and at clinic entrance, and birth cohort (standardized beta = 0.033 and -0.022, respectively), Lize F. van Vulpen, MD, of University Medical Center Utrecht, the Netherlands, reported at the annual meeting of the European Association of Haemophilia and Allied Disorders.

Study subjects had a median age of 43 years, median AJBRs of 2.5 and 0.5 for severe and moderate disease, respectively, and median Pettersson scores of 22 and 4 in the groups, respectively. An HFE mutation was detected in 91 patients, and their levels of ferritin, iron, and transferrin saturation were significantly increased, but other baseline characteristic were similar in those with and without HFE mutation, and regardless of (GT)n-repeat length.

The marked heterogeneity in joint damage seen among hemophilia patients was hypothesized in this study to be associated with differences in iron handling, but the findings failed to support that hypothesis, Dr. van Vulpen concluded.

Dr. van Vulpen reported having no disclosures.

[email protected]

Carriers of a hemochromatosis (HFE) gene mutation or a long (GT)n-repeat length within the HMOX1 promoter regions did not appear to have an increase in hemophilic arthropathy.

In 201 blood samples from patients with severe hemophilia A or B and 37 from patients with moderate disease, neither the presence of an HFE mutation nor a long (GT)n-repeat length was associated with an increase in joint damage. The assessment was based on Pettersson score after adjustment for disease severity, presence of inhibitors, annual joint bleeding rate (AJBR), age at Pettersson score and at clinic entrance, and birth cohort (standardized beta = 0.033 and -0.022, respectively), Lize F. van Vulpen, MD, of University Medical Center Utrecht, the Netherlands, reported at the annual meeting of the European Association of Haemophilia and Allied Disorders.

Study subjects had a median age of 43 years, median AJBRs of 2.5 and 0.5 for severe and moderate disease, respectively, and median Pettersson scores of 22 and 4 in the groups, respectively. An HFE mutation was detected in 91 patients, and their levels of ferritin, iron, and transferrin saturation were significantly increased, but other baseline characteristic were similar in those with and without HFE mutation, and regardless of (GT)n-repeat length.

The marked heterogeneity in joint damage seen among hemophilia patients was hypothesized in this study to be associated with differences in iron handling, but the findings failed to support that hypothesis, Dr. van Vulpen concluded.

Dr. van Vulpen reported having no disclosures.

[email protected]

Human-cl rhFVIII, a new generation recombinant factor VIII of human origin, appears to be associated with a low inhibitor incidence in patients with severe hemophilia A, according to interim findings from the ongoing NuProtect study.

In 66 evaluable previously untreated patients with at least 20 days of exposure to human-cl rhFVIII, the cumulative incidence of high-titer and low-titer inhibitor development was 12.8% and 8.4%, respectively, Ellis J. Neufeld, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.

The median age at first treatment was 13 months (range of 3-135 months). Of 59 patients with available F8 gene analysis, 44 had high-risk mutations and 47 had null mutations; 1 had no mutation identified. After a median of 11.5 treatment exposure days, 8 of the 66 patients developed high-titer inhibitors and 5 developed low-titer inhibitors; 4 of those were transient, said Dr. Neufeld of Harvard Medical School, Boston.

Only two of the patients developed an inhibitor, including one high- and one low-titer inhibitor, after 20 exposure days. Among the 13 inhibitor patients, 12 had an F8 mutation identified; all were null, and 11 were high risk.

In a prior study of 201 patients with previously treated severe hemophilia A, no inhibitors were reported with human-cl rhFVIII – which is produced in human cells without chemical modification or protein fusion. The NuProtect study is looking at immunogenicity, efficacy, and safety in previously untreated patients. Final data are expected in 2018, Dr. Neufeld noted.

Dr. Neufeld disclosed financial ties to Octapharma, the sponsor of NuProtect, and numerous other pharmaceutical companies.

[email protected]

Human-cl rhFVIII, a new generation recombinant factor VIII of human origin, appears to be associated with a low inhibitor incidence in patients with severe hemophilia A, according to interim findings from the ongoing NuProtect study.

In 66 evaluable previously untreated patients with at least 20 days of exposure to human-cl rhFVIII, the cumulative incidence of high-titer and low-titer inhibitor development was 12.8% and 8.4%, respectively, Ellis J. Neufeld, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.

The median age at first treatment was 13 months (range of 3-135 months). Of 59 patients with available F8 gene analysis, 44 had high-risk mutations and 47 had null mutations; 1 had no mutation identified. After a median of 11.5 treatment exposure days, 8 of the 66 patients developed high-titer inhibitors and 5 developed low-titer inhibitors; 4 of those were transient, said Dr. Neufeld of Harvard Medical School, Boston.

Only two of the patients developed an inhibitor, including one high- and one low-titer inhibitor, after 20 exposure days. Among the 13 inhibitor patients, 12 had an F8 mutation identified; all were null, and 11 were high risk.

In a prior study of 201 patients with previously treated severe hemophilia A, no inhibitors were reported with human-cl rhFVIII – which is produced in human cells without chemical modification or protein fusion. The NuProtect study is looking at immunogenicity, efficacy, and safety in previously untreated patients. Final data are expected in 2018, Dr. Neufeld noted.

Dr. Neufeld disclosed financial ties to Octapharma, the sponsor of NuProtect, and numerous other pharmaceutical companies.

[email protected]

Human-cl rhFVIII, a new generation recombinant factor VIII of human origin, appears to be associated with a low inhibitor incidence in patients with severe hemophilia A, according to interim findings from the ongoing NuProtect study.

In 66 evaluable previously untreated patients with at least 20 days of exposure to human-cl rhFVIII, the cumulative incidence of high-titer and low-titer inhibitor development was 12.8% and 8.4%, respectively, Ellis J. Neufeld, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.

The median age at first treatment was 13 months (range of 3-135 months). Of 59 patients with available F8 gene analysis, 44 had high-risk mutations and 47 had null mutations; 1 had no mutation identified. After a median of 11.5 treatment exposure days, 8 of the 66 patients developed high-titer inhibitors and 5 developed low-titer inhibitors; 4 of those were transient, said Dr. Neufeld of Harvard Medical School, Boston.

Only two of the patients developed an inhibitor, including one high- and one low-titer inhibitor, after 20 exposure days. Among the 13 inhibitor patients, 12 had an F8 mutation identified; all were null, and 11 were high risk.

In a prior study of 201 patients with previously treated severe hemophilia A, no inhibitors were reported with human-cl rhFVIII – which is produced in human cells without chemical modification or protein fusion. The NuProtect study is looking at immunogenicity, efficacy, and safety in previously untreated patients. Final data are expected in 2018, Dr. Neufeld noted.

Dr. Neufeld disclosed financial ties to Octapharma, the sponsor of NuProtect, and numerous other pharmaceutical companies.

[email protected]

SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.

The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.

Bruce Jancin/Frontline Medical News

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SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.

The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.

Bruce Jancin/Frontline Medical News

[email protected]

SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.

The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.

Bruce Jancin/Frontline Medical News

[email protected]

Proton pump inhibitors (PPIs) are one of the most frequently used drug classes, given that they are readily accessible over-the-counter as well as via prescription. About 100 million PPI prescriptions dispensed annually.¹ One study showed that between 25% and 70% of patients taking a PPI do not have an appropriate indication.² It is common for patients to be prescribed a PPI during and following an inpatient hospital stay. Upon discharge, many of these patients continue taking PPIs without proper documentation or a planned termination date.

The human stomach uses 3 primary neurotransmitters that regulate gastric acid secretion: acetylcholine (ACh), histamine (H), and gastrin (G). The interactions between these neurotransmitters promote and inhibit hydrogen ion (H⁺) generation. Stimulation of their corresponding receptors draws H⁺ into parietal cells that line the stomach. Once in the cell, a H⁺-K⁺-ATPase (more commonly known as the proton pump) actively transports H⁺ into the lumen of the stomach. The H⁺ bind with chlorine ions to form hydrochloric acid, which increases stomach acidity.⁵ Histamine receptors were thought to be responsible for the greatest degree of stimulation. Hence, histamine type 2-receptor antagonists (H₂RAs) became a novel means of therapy to reduce stomach acidity. While utilizing H₂RAs was effective, it was theorized the downstream inhibition of the action of all 3 neurotransmitters would serve as a more successful therapy. Therefore, PPIs were developed to target the H⁺-K⁺-ATPase Over the past decade, many studies have evaluated the long-term PPI adverse effects (AEs). These include calcium and magnesium malabsorption, vitamin B₁₂ deficiency, Clostridium difficile (C difficile) associated disease (CDAD), and community-acquired pneumonia (CAP). Within the past year, data have become available linking PPI use to dementia and chronic kidney disease (CKD).^3,4 The following article reviews literature on the safety of long-term PPI use and proposes recommendations for proper use for their most common indications.

Malabsorption

Calcium & Long-Term Fracture Risk

Calcium is an essential component in bone health and formation. In fact, 99% of all calcium found in the body is stored in bones.⁶ The primary source of calcium is through diet and oral supplements. After it is ingested, calcium is absorbed from the stomach into the blood in a pH dependent manner. If the pH of the stomach is too high (ie, too basic) calcium is not absorbed into blood and remains in the gastrointestinal (GI) tract for fecal excretion. Without sufficient calcium, the body’s osteoclasts and osteoblasts remain inactive, which hinders proper bone turnover.⁷

The decrease in acidity leads to calcium malabsorption and increases fracture risk long- term.⁸ Khalili and colleagues surveyed 80,000 postmenopausal women to measure the incidence of hip fracture in women taking PPIs. The study found that there was a 35% increase in risk of hip fracture among women who regularly used PPIs for at least 2 years (age-adjusted hazard ratio [HR] 1.35; 95% confidence interval [CI], 1.13 -1.62). Adjusted HRs for 4-year and 6- to 8-year use of a PPI was 1.42 (95% CI, 1.05-1.93) and 1.55 (95% CI, 1.03-2.32), respectively, indicating that the longer women were on PPI therapy, the higher the risk of hip fracture. The study also evaluated the time since stopping PPI and the risk of hip fracture. Women who stopped PPI use more than 2 years prior had a similar risk to that of women who never used a PPI, indicating that the effect was reversible.⁹

Magnesium

Magnesium is an important intracellular ion that has a number of key functions in metabolism and ion transport in the human body. Once ingested, magnesium is absorbed into the bloodstream from the small and large intestines via passive and active transport. Transient receptor potential melastatin 6 (TRPM6) is one of the essential proteins that serve as a transporter for magnesium.¹⁰ The high affinity for magnesium of these transporters allows them to maintain adequate levels of magnesium in the blood. In states of low magnesium (hypomagnesemia), the body is at risk for many AEs including seizures, arrhythmias, tetany, and hypotension.¹¹

Proton pump inhibitors have been linked to hypomagnesemia, and recent evaluation has clarified a potential mechanism.¹² TRPM6 activity is increased in an acidic environment. When a PPI increases the pH of the stomach, TRPM6 and magnesium levels decrease.¹² Luk and colleagues identified 66,102 subjects experiencing AEs while taking a PPI. Hypomagnesemia had a prevalence rate of 1% in these patients. According to the researchers, PPIs were associated with hypomagnesemia and that pantoprazole had the highest incidence among all other PPIs studied (OR, 4.3; 95% CI, 3.3 – 5.7; P < .001).¹³

Vitamin B₁₂

In recent years, vitamin B₁₂ has been the subject of many studies. An area of concern is vitamin B₁₂’s neurologic effect, as it has been successfully demonstrated that vitamin B₁₂ is essential for proper cognitive function.¹⁴ Some data suggest that degeneration is present in parts of the spinal column in patients with cognitive decline or neurologic problems. These lesions are due to improper myelin formation and are specific to vitamin B₁₂ deficiency.¹⁵ In 2013 the CDC published the Healthy Brain Initiative, which stated cognitive impairment can be caused by vitamin B₁₂ deficiency.¹⁶

Similar to calcium, vitamin B₁₂ needs an acidic environment to be digested and absorbed.¹⁷ Vitamin B₁₂ is released from food proteins via gastric acid and pepsin. Once free, the vitamin B₁₂ pairs with R-binders secreted in the stomach. Pancreatic enzymes then degrade this complex into a form that can be absorbed into circulation by the intestine. Given that PPIs reduce the acidity of the stomach, they also reduce the body’s ability to release vitamin B₁₂ from food proteins and be paired with the R-binders.¹⁸

In 2013, Lam and colleagues evaluated the association between vitamin B₁₂ deficiency and the use of PPIs and H₂RAs. An extensive evaluation was performed on 25,956 patients with a diagnosis of vitamin B₁₂ deficiency and 184,199 patients without. About 12% of patients with vitamin B₁₂ deficiency had received more than a 2-year supply of a PPI, whereas only 7.2% of the patients without vitamin B₁₂ deficiency received a 2-year supply of a PPI. Four point 3 percent of patients with vitamin B₁₂ deficiency received more than a 2-year supply of an H₂RA. Only 3.2% of patients without vitamin B₁₂ deficiency received more than a 2-year supply of H₂RA. The study concluded that a 2-year or greater history of PPI (OR, 1.65; 95% CI, 1.58-1.73) or H₂RA (OR, 1.25; 95% CI, 1.17-1.34) use was associated with vitamin B₁₂ deficiency.¹⁹

PPIs and Infections

Clostridium difficile-associated disease

Nationwide CDAD has become a prevalent infection nationwide. In 2011, C difficile caused nearly 500,000 infections and was associated with 29,000 deaths in the U.S.²⁰ One study stated that C difficile is the third most common cause of infectious diarrhea in people aged >75 years.²¹

C difficile is part of the body’s normal flora in the large intestine. It grows and colonizes in an environment of low acidity. Therefore, in the stomach, where the pH is relatively low, C difficile is unable to colonize.²² When a PPI is introduced, the increased gastric pH increases the risk for CDAD.

Dial and colleagues conducted a multicenter case control study to determine whether gastric acid suppression increases the risk of CDAD. Compared with patients who did not take a gastric acid suppressant, those taking a PPI had a 2.9-fold increase in developing CDAD (95% CI, 2.4-3.4). Comparatively, H₂RAs had a 2.0-fold increase for CDAD (95% CI, 1.6 to 2.7). These results correlated with the fact that PPIs have a greater impact on gastric pH than do H₂RAs.²³

Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) has become a growing concern in the U.S. According to the Infectious Disease Society of America (IDSA) and American Thoracic clinical consensus guidelines, CAP remains one of the top reasons for hospitalizations in the U.S., and about 10% of patients admitted to the hospital for CAP end up in the intensive care unit (ICU).²⁴ In the past, PPIs have been linked to patients’ predisposal for developingCAP.²⁵ Although controversial, available evidence suggests a direct association. In 2008 Sarker and colleagues theorized a mechanism that the acid reduction of the gastric lumen allows for increased bacterial colonization in the upper part of the GI tract.²⁶ Since the acidity of the stomach serves as a defense mechanism against many ingested bacteria, many pathogens will be able to survive in the more basic environment.²⁵

Sarkar and colleagues went on to evaluate 80,000 cases over 15 years. The objective was to examine the association between PPI use and the date of diagnosis of the CAP infection, known as the index date. The study demonstrated that PPI use was not associated with increased CAP risk in the long-term (adjusted odds ratio (OR), 1.02; 95% CI, 0.97-1.08). The study did find a strong increase in the risk of CAP if a PPI was started within 2 days (adjusted OR, 6.53; 95% CI, 3.95-10.80), 7 days (adjusted OR, 3.79; 95% CI, 2.66-5.42), and 14 days (adjusted OR, 3.21; 95% CI, 2.46-4.18) of the index date.²⁶

Four years later, de Jagar and colleagues examined the differences in microbial etiology in CAP patients with and without an active PPI. Over a 4-year study period, 463 individuals were selected with clinical suspicion of CAP. The microbial etiology could be determined in 70% of those patients. The remaining 30% were excluded due to an alternative diagnosis. One of the most likely pathogens to cause a CAP infection is Streptococcus pneumoniae (S pneumonia).²⁷ Patients prescribed a PPI were significantly more likely to be infected with S pneumoniae than those not prescribed a PPI (28% vs 11%). The study concluded that the risk of S pneumoniae in patients taking a PPI was 2.23 times more likely (95% CI, 1.28-3.75).²⁸

Dementia

In 2040, it is estimated that more than 80 million people will have from dementia.²⁹ This is expected to become a large fiscal burden on the health care system. In 2010, about $604 billion was spent on therapy for dementia worldwide.³⁰ Although no cure for dementia exists, it is more feasible than in previous years to prevent its occurrence. However, many medications, including PPIs, are associated with the development of dementia; therefore, it is important to minimize their use when possible.

As noted earlier vitamin B₁₂ deficiency may lead to cognitive decline. Due to the malabsorption of vitamin B₁₂ that results from PPI use, it is hypothesized that PPIs may be associated with incidence of dementia. Badiola and colleagues discovered that in the brains of mice given a PPI, levels of β-amyloid increased significantly affecting enzymes responsible for cognition.³¹ In a February 2016, JAMA article, researchers conducted a prospective cohort study evaluating 73,679 patients aged ≥75 years with no dementia at baseline. They went on to assess regular use of a PPI, defined as at least 1 PPI prescription every 3 months, and the incidence of dementia. Patients with regular use of a PPI (≥ 1 PPI prescription every 3 months) had a 44% increase risk of incident dementia (HR, 1.44; 95% CI, 1.36-1.52; P < .001).³ Therefore, it is theorized that avoiding PPI use in the elderly may prevent the development of dementia.

Chronic Kidney Disease

The prevalence of CKD has drastically increased in recent decades. It is estimated that up to 13% of people in the U.S. are affected by CKD.³² Some studies suggest that dosing errors occur at much higher rates in patients with declined glomerular filtration rate (GFR).³³ The correct utilization use of medications becomes especially pertinent to this population. Several studies have already linked PPI use to acute interstitial nephritis (AIN) and acute kidney injury (AKI).^34-36

Lazarus and colleagues evaluated the association between PPI use and the incidence of CKD. Their analysis was performed in a long-term running population-based cohort and replicated in a separate health care system. In the running cohort, patients receiving a PPI had a 1.45-fold greater chance of developing CKD (95% CI, 1.11-1.90; P = .006). In that same cohort, patients on a PPI had a 1.72-fold increase risk of AKI (95% CI, 1.28-2.30; P < .001).⁴ Similar outcomes were seen in the replicated cohort. However, the replicated cohort did observe that twice daily dosing of a PPI (adjusted HR, 1.46; CI, 1.28-1.67; P < .001) had a stronger association with CKD than once- daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21; P < .001). H₂RAs exhibited no association with CKD in the running cohort (HR, 1.15; 97% CI, 0.98-1.36; P = .10) or the replication cohort (HR, 0.93; 95% CI, 0.88-0.99; P = .03).⁴

Clinical PPI Recommendations

There are several FDA-approved and unapproved indications that warrant PPI therapy. Proton pump inhibitor indications include gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), Helicobacter pylori, and ulcers associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

GERD Recommendations

Optimal dosing and duration is important with all medications to maximize efficacy and minimize toxicity. In the case of PPIs, dosing and duration are of particularly concern due to the aforementioned AEs. Table illustrates manufacturer-recommended dosing and duration for the most commonly prescribed PPIs. Although these dosing regimens are based on clinical studies, PPIs are commonly prescribed at higher doses and for longer durations. By extending the duration of therapy, the risk of potential long-term AEs increases dramatically. If durations are limited to the recommended window, risk of AEs can be reduced.

Alternative Therapies

There are several strategies that exist to limit the use of PPIs, including lifestyle modifications to prevent GERD, supplementation of an alternative agent to prevent high doses of the PPI, or discontinuing PPI therapy all together. Lifestyle modifications provide additional benefit as monotherapy or to supplement a pharmacologic regimen.

The American Journal of Gastroenterology promoted lifestyle modifications that include:

• Weight loss for patients with GERD who are overweight and had a recent weight gain;
• Elevation of the head of the bed (if nighttime symptoms present);
• Elimination of dietary triggers;
• Fatty foods, caffeine, chocolate, spicy food, food with high fat content, carbonated beverages, and peppermint;
• Avoiding tight fitting garments to prevent increase in gastric pressure;
• Promote salivation through oral lozenges or chewing gum to neutralize refluxed acid;
• Avoidance of tobacco and alcohol; and
• Abdominal breathing exercise to strengthen the barrier of the lower esophageal sphincter.³⁷

The above modifications may reduce the need for pharmacologic therapy, thereby reducing possible of long-term AEs.

If lifestyle modifications alone are not enough, it is reasonable to use a H₂RA for acute symptom relief or reduce high doses and frequencies of a PPI. H₂RAs are well studied and effective in the management of GERD. According to the American College of Gastroenterology 2013 clinical practice guidelines, H₂RAs can serve as an effective maintenance medication to relieve heartburn in patients without erosive disease. The guideline also states that a bedtime H₂RA can be used to supplement a once- daily daytime PPI if nighttime reflux exists. This can eliminate the need to exceed manufacturer-recommended doses.³⁷

One of the final challenges to overcome is a patient that has been maintained on chronic PPI therapy. However, caution should be exercised if choosing to discontinue a PPI. In a study by Niklesson and colleagues, after a 4-week course of pantoprazole given to healthy volunteers, those patients with no preexisting symptoms developed dyspeptic symptoms of GERD, such as heartburn, indigestion, and stomach discomfort. This correlation suggests that a rebound hypersecretion occurs after prolonged suppression of the proton pump, and therefore a gradual taper should be used.³⁸ Although no definitive national recommendations on how to taper a patient off of a PPI exist, one suggestion is a 2- to 3-week taper by using a half-dose once daily or full dose on alternate days.³⁹ This strategy has exhibited moderate success rates when used. Oral and written education on symptom management and the administration of H₂RAs for infrequent breakthrough symptoms supplemented the reduction of the PPI.

Conclusion

Proton pump inhibitors have become a popular and effective drug class for a multitude of indications. However, it is crucial to recognize the risk of long-term use. It is important to properly assess the need for a PPI and to use appropriate dosing and duration, since prolonged durations and doses above the manufacturer’s recommendations is a primary contributor to long-term consequences. Both package inserts and clinical guidelines serve as valuable resources to help balance the risks and benefits of this medication class and can help guide therapeutic decisions.

Proton pump inhibitors (PPIs) are one of the most frequently used drug classes, given that they are readily accessible over-the-counter as well as via prescription. About 100 million PPI prescriptions dispensed annually.¹ One study showed that between 25% and 70% of patients taking a PPI do not have an appropriate indication.² It is common for patients to be prescribed a PPI during and following an inpatient hospital stay. Upon discharge, many of these patients continue taking PPIs without proper documentation or a planned termination date.

The human stomach uses 3 primary neurotransmitters that regulate gastric acid secretion: acetylcholine (ACh), histamine (H), and gastrin (G). The interactions between these neurotransmitters promote and inhibit hydrogen ion (H⁺) generation. Stimulation of their corresponding receptors draws H⁺ into parietal cells that line the stomach. Once in the cell, a H⁺-K⁺-ATPase (more commonly known as the proton pump) actively transports H⁺ into the lumen of the stomach. The H⁺ bind with chlorine ions to form hydrochloric acid, which increases stomach acidity.⁵ Histamine receptors were thought to be responsible for the greatest degree of stimulation. Hence, histamine type 2-receptor antagonists (H₂RAs) became a novel means of therapy to reduce stomach acidity. While utilizing H₂RAs was effective, it was theorized the downstream inhibition of the action of all 3 neurotransmitters would serve as a more successful therapy. Therefore, PPIs were developed to target the H⁺-K⁺-ATPase Over the past decade, many studies have evaluated the long-term PPI adverse effects (AEs). These include calcium and magnesium malabsorption, vitamin B₁₂ deficiency, Clostridium difficile (C difficile) associated disease (CDAD), and community-acquired pneumonia (CAP). Within the past year, data have become available linking PPI use to dementia and chronic kidney disease (CKD).^3,4 The following article reviews literature on the safety of long-term PPI use and proposes recommendations for proper use for their most common indications.

Malabsorption

Calcium & Long-Term Fracture Risk

Calcium is an essential component in bone health and formation. In fact, 99% of all calcium found in the body is stored in bones.⁶ The primary source of calcium is through diet and oral supplements. After it is ingested, calcium is absorbed from the stomach into the blood in a pH dependent manner. If the pH of the stomach is too high (ie, too basic) calcium is not absorbed into blood and remains in the gastrointestinal (GI) tract for fecal excretion. Without sufficient calcium, the body’s osteoclasts and osteoblasts remain inactive, which hinders proper bone turnover.⁷

The decrease in acidity leads to calcium malabsorption and increases fracture risk long- term.⁸ Khalili and colleagues surveyed 80,000 postmenopausal women to measure the incidence of hip fracture in women taking PPIs. The study found that there was a 35% increase in risk of hip fracture among women who regularly used PPIs for at least 2 years (age-adjusted hazard ratio [HR] 1.35; 95% confidence interval [CI], 1.13 -1.62). Adjusted HRs for 4-year and 6- to 8-year use of a PPI was 1.42 (95% CI, 1.05-1.93) and 1.55 (95% CI, 1.03-2.32), respectively, indicating that the longer women were on PPI therapy, the higher the risk of hip fracture. The study also evaluated the time since stopping PPI and the risk of hip fracture. Women who stopped PPI use more than 2 years prior had a similar risk to that of women who never used a PPI, indicating that the effect was reversible.⁹

Magnesium

Magnesium is an important intracellular ion that has a number of key functions in metabolism and ion transport in the human body. Once ingested, magnesium is absorbed into the bloodstream from the small and large intestines via passive and active transport. Transient receptor potential melastatin 6 (TRPM6) is one of the essential proteins that serve as a transporter for magnesium.¹⁰ The high affinity for magnesium of these transporters allows them to maintain adequate levels of magnesium in the blood. In states of low magnesium (hypomagnesemia), the body is at risk for many AEs including seizures, arrhythmias, tetany, and hypotension.¹¹

Proton pump inhibitors have been linked to hypomagnesemia, and recent evaluation has clarified a potential mechanism.¹² TRPM6 activity is increased in an acidic environment. When a PPI increases the pH of the stomach, TRPM6 and magnesium levels decrease.¹² Luk and colleagues identified 66,102 subjects experiencing AEs while taking a PPI. Hypomagnesemia had a prevalence rate of 1% in these patients. According to the researchers, PPIs were associated with hypomagnesemia and that pantoprazole had the highest incidence among all other PPIs studied (OR, 4.3; 95% CI, 3.3 – 5.7; P < .001).¹³

Vitamin B₁₂

In recent years, vitamin B₁₂ has been the subject of many studies. An area of concern is vitamin B₁₂’s neurologic effect, as it has been successfully demonstrated that vitamin B₁₂ is essential for proper cognitive function.¹⁴ Some data suggest that degeneration is present in parts of the spinal column in patients with cognitive decline or neurologic problems. These lesions are due to improper myelin formation and are specific to vitamin B₁₂ deficiency.¹⁵ In 2013 the CDC published the Healthy Brain Initiative, which stated cognitive impairment can be caused by vitamin B₁₂ deficiency.¹⁶

Similar to calcium, vitamin B₁₂ needs an acidic environment to be digested and absorbed.¹⁷ Vitamin B₁₂ is released from food proteins via gastric acid and pepsin. Once free, the vitamin B₁₂ pairs with R-binders secreted in the stomach. Pancreatic enzymes then degrade this complex into a form that can be absorbed into circulation by the intestine. Given that PPIs reduce the acidity of the stomach, they also reduce the body’s ability to release vitamin B₁₂ from food proteins and be paired with the R-binders.¹⁸

In 2013, Lam and colleagues evaluated the association between vitamin B₁₂ deficiency and the use of PPIs and H₂RAs. An extensive evaluation was performed on 25,956 patients with a diagnosis of vitamin B₁₂ deficiency and 184,199 patients without. About 12% of patients with vitamin B₁₂ deficiency had received more than a 2-year supply of a PPI, whereas only 7.2% of the patients without vitamin B₁₂ deficiency received a 2-year supply of a PPI. Four point 3 percent of patients with vitamin B₁₂ deficiency received more than a 2-year supply of an H₂RA. Only 3.2% of patients without vitamin B₁₂ deficiency received more than a 2-year supply of H₂RA. The study concluded that a 2-year or greater history of PPI (OR, 1.65; 95% CI, 1.58-1.73) or H₂RA (OR, 1.25; 95% CI, 1.17-1.34) use was associated with vitamin B₁₂ deficiency.¹⁹

PPIs and Infections

Clostridium difficile-associated disease

Nationwide CDAD has become a prevalent infection nationwide. In 2011, C difficile caused nearly 500,000 infections and was associated with 29,000 deaths in the U.S.²⁰ One study stated that C difficile is the third most common cause of infectious diarrhea in people aged >75 years.²¹

C difficile is part of the body’s normal flora in the large intestine. It grows and colonizes in an environment of low acidity. Therefore, in the stomach, where the pH is relatively low, C difficile is unable to colonize.²² When a PPI is introduced, the increased gastric pH increases the risk for CDAD.

Dial and colleagues conducted a multicenter case control study to determine whether gastric acid suppression increases the risk of CDAD. Compared with patients who did not take a gastric acid suppressant, those taking a PPI had a 2.9-fold increase in developing CDAD (95% CI, 2.4-3.4). Comparatively, H₂RAs had a 2.0-fold increase for CDAD (95% CI, 1.6 to 2.7). These results correlated with the fact that PPIs have a greater impact on gastric pH than do H₂RAs.²³

Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) has become a growing concern in the U.S. According to the Infectious Disease Society of America (IDSA) and American Thoracic clinical consensus guidelines, CAP remains one of the top reasons for hospitalizations in the U.S., and about 10% of patients admitted to the hospital for CAP end up in the intensive care unit (ICU).²⁴ In the past, PPIs have been linked to patients’ predisposal for developingCAP.²⁵ Although controversial, available evidence suggests a direct association. In 2008 Sarker and colleagues theorized a mechanism that the acid reduction of the gastric lumen allows for increased bacterial colonization in the upper part of the GI tract.²⁶ Since the acidity of the stomach serves as a defense mechanism against many ingested bacteria, many pathogens will be able to survive in the more basic environment.²⁵

Sarkar and colleagues went on to evaluate 80,000 cases over 15 years. The objective was to examine the association between PPI use and the date of diagnosis of the CAP infection, known as the index date. The study demonstrated that PPI use was not associated with increased CAP risk in the long-term (adjusted odds ratio (OR), 1.02; 95% CI, 0.97-1.08). The study did find a strong increase in the risk of CAP if a PPI was started within 2 days (adjusted OR, 6.53; 95% CI, 3.95-10.80), 7 days (adjusted OR, 3.79; 95% CI, 2.66-5.42), and 14 days (adjusted OR, 3.21; 95% CI, 2.46-4.18) of the index date.²⁶

Four years later, de Jagar and colleagues examined the differences in microbial etiology in CAP patients with and without an active PPI. Over a 4-year study period, 463 individuals were selected with clinical suspicion of CAP. The microbial etiology could be determined in 70% of those patients. The remaining 30% were excluded due to an alternative diagnosis. One of the most likely pathogens to cause a CAP infection is Streptococcus pneumoniae (S pneumonia).²⁷ Patients prescribed a PPI were significantly more likely to be infected with S pneumoniae than those not prescribed a PPI (28% vs 11%). The study concluded that the risk of S pneumoniae in patients taking a PPI was 2.23 times more likely (95% CI, 1.28-3.75).²⁸

Dementia

In 2040, it is estimated that more than 80 million people will have from dementia.²⁹ This is expected to become a large fiscal burden on the health care system. In 2010, about $604 billion was spent on therapy for dementia worldwide.³⁰ Although no cure for dementia exists, it is more feasible than in previous years to prevent its occurrence. However, many medications, including PPIs, are associated with the development of dementia; therefore, it is important to minimize their use when possible.

As noted earlier vitamin B₁₂ deficiency may lead to cognitive decline. Due to the malabsorption of vitamin B₁₂ that results from PPI use, it is hypothesized that PPIs may be associated with incidence of dementia. Badiola and colleagues discovered that in the brains of mice given a PPI, levels of β-amyloid increased significantly affecting enzymes responsible for cognition.³¹ In a February 2016, JAMA article, researchers conducted a prospective cohort study evaluating 73,679 patients aged ≥75 years with no dementia at baseline. They went on to assess regular use of a PPI, defined as at least 1 PPI prescription every 3 months, and the incidence of dementia. Patients with regular use of a PPI (≥ 1 PPI prescription every 3 months) had a 44% increase risk of incident dementia (HR, 1.44; 95% CI, 1.36-1.52; P < .001).³ Therefore, it is theorized that avoiding PPI use in the elderly may prevent the development of dementia.

Chronic Kidney Disease

The prevalence of CKD has drastically increased in recent decades. It is estimated that up to 13% of people in the U.S. are affected by CKD.³² Some studies suggest that dosing errors occur at much higher rates in patients with declined glomerular filtration rate (GFR).³³ The correct utilization use of medications becomes especially pertinent to this population. Several studies have already linked PPI use to acute interstitial nephritis (AIN) and acute kidney injury (AKI).^34-36

Lazarus and colleagues evaluated the association between PPI use and the incidence of CKD. Their analysis was performed in a long-term running population-based cohort and replicated in a separate health care system. In the running cohort, patients receiving a PPI had a 1.45-fold greater chance of developing CKD (95% CI, 1.11-1.90; P = .006). In that same cohort, patients on a PPI had a 1.72-fold increase risk of AKI (95% CI, 1.28-2.30; P < .001).⁴ Similar outcomes were seen in the replicated cohort. However, the replicated cohort did observe that twice daily dosing of a PPI (adjusted HR, 1.46; CI, 1.28-1.67; P < .001) had a stronger association with CKD than once- daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21; P < .001). H₂RAs exhibited no association with CKD in the running cohort (HR, 1.15; 97% CI, 0.98-1.36; P = .10) or the replication cohort (HR, 0.93; 95% CI, 0.88-0.99; P = .03).⁴

Clinical PPI Recommendations

There are several FDA-approved and unapproved indications that warrant PPI therapy. Proton pump inhibitor indications include gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), Helicobacter pylori, and ulcers associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

GERD Recommendations

Optimal dosing and duration is important with all medications to maximize efficacy and minimize toxicity. In the case of PPIs, dosing and duration are of particularly concern due to the aforementioned AEs. Table illustrates manufacturer-recommended dosing and duration for the most commonly prescribed PPIs. Although these dosing regimens are based on clinical studies, PPIs are commonly prescribed at higher doses and for longer durations. By extending the duration of therapy, the risk of potential long-term AEs increases dramatically. If durations are limited to the recommended window, risk of AEs can be reduced.

Alternative Therapies

There are several strategies that exist to limit the use of PPIs, including lifestyle modifications to prevent GERD, supplementation of an alternative agent to prevent high doses of the PPI, or discontinuing PPI therapy all together. Lifestyle modifications provide additional benefit as monotherapy or to supplement a pharmacologic regimen.

The American Journal of Gastroenterology promoted lifestyle modifications that include:

• Weight loss for patients with GERD who are overweight and had a recent weight gain;
• Elevation of the head of the bed (if nighttime symptoms present);
• Elimination of dietary triggers;
• Fatty foods, caffeine, chocolate, spicy food, food with high fat content, carbonated beverages, and peppermint;
• Avoiding tight fitting garments to prevent increase in gastric pressure;
• Promote salivation through oral lozenges or chewing gum to neutralize refluxed acid;
• Avoidance of tobacco and alcohol; and
• Abdominal breathing exercise to strengthen the barrier of the lower esophageal sphincter.³⁷

The above modifications may reduce the need for pharmacologic therapy, thereby reducing possible of long-term AEs.

If lifestyle modifications alone are not enough, it is reasonable to use a H₂RA for acute symptom relief or reduce high doses and frequencies of a PPI. H₂RAs are well studied and effective in the management of GERD. According to the American College of Gastroenterology 2013 clinical practice guidelines, H₂RAs can serve as an effective maintenance medication to relieve heartburn in patients without erosive disease. The guideline also states that a bedtime H₂RA can be used to supplement a once- daily daytime PPI if nighttime reflux exists. This can eliminate the need to exceed manufacturer-recommended doses.³⁷

One of the final challenges to overcome is a patient that has been maintained on chronic PPI therapy. However, caution should be exercised if choosing to discontinue a PPI. In a study by Niklesson and colleagues, after a 4-week course of pantoprazole given to healthy volunteers, those patients with no preexisting symptoms developed dyspeptic symptoms of GERD, such as heartburn, indigestion, and stomach discomfort. This correlation suggests that a rebound hypersecretion occurs after prolonged suppression of the proton pump, and therefore a gradual taper should be used.³⁸ Although no definitive national recommendations on how to taper a patient off of a PPI exist, one suggestion is a 2- to 3-week taper by using a half-dose once daily or full dose on alternate days.³⁹ This strategy has exhibited moderate success rates when used. Oral and written education on symptom management and the administration of H₂RAs for infrequent breakthrough symptoms supplemented the reduction of the PPI.

Conclusion

Proton pump inhibitors have become a popular and effective drug class for a multitude of indications. However, it is crucial to recognize the risk of long-term use. It is important to properly assess the need for a PPI and to use appropriate dosing and duration, since prolonged durations and doses above the manufacturer’s recommendations is a primary contributor to long-term consequences. Both package inserts and clinical guidelines serve as valuable resources to help balance the risks and benefits of this medication class and can help guide therapeutic decisions.

Proton pump inhibitors (PPIs) are one of the most frequently used drug classes, given that they are readily accessible over-the-counter as well as via prescription. About 100 million PPI prescriptions dispensed annually.¹ One study showed that between 25% and 70% of patients taking a PPI do not have an appropriate indication.² It is common for patients to be prescribed a PPI during and following an inpatient hospital stay. Upon discharge, many of these patients continue taking PPIs without proper documentation or a planned termination date.

The human stomach uses 3 primary neurotransmitters that regulate gastric acid secretion: acetylcholine (ACh), histamine (H), and gastrin (G). The interactions between these neurotransmitters promote and inhibit hydrogen ion (H⁺) generation. Stimulation of their corresponding receptors draws H⁺ into parietal cells that line the stomach. Once in the cell, a H⁺-K⁺-ATPase (more commonly known as the proton pump) actively transports H⁺ into the lumen of the stomach. The H⁺ bind with chlorine ions to form hydrochloric acid, which increases stomach acidity.⁵ Histamine receptors were thought to be responsible for the greatest degree of stimulation. Hence, histamine type 2-receptor antagonists (H₂RAs) became a novel means of therapy to reduce stomach acidity. While utilizing H₂RAs was effective, it was theorized the downstream inhibition of the action of all 3 neurotransmitters would serve as a more successful therapy. Therefore, PPIs were developed to target the H⁺-K⁺-ATPase Over the past decade, many studies have evaluated the long-term PPI adverse effects (AEs). These include calcium and magnesium malabsorption, vitamin B₁₂ deficiency, Clostridium difficile (C difficile) associated disease (CDAD), and community-acquired pneumonia (CAP). Within the past year, data have become available linking PPI use to dementia and chronic kidney disease (CKD).^3,4 The following article reviews literature on the safety of long-term PPI use and proposes recommendations for proper use for their most common indications.

Malabsorption

Calcium & Long-Term Fracture Risk

Calcium is an essential component in bone health and formation. In fact, 99% of all calcium found in the body is stored in bones.⁶ The primary source of calcium is through diet and oral supplements. After it is ingested, calcium is absorbed from the stomach into the blood in a pH dependent manner. If the pH of the stomach is too high (ie, too basic) calcium is not absorbed into blood and remains in the gastrointestinal (GI) tract for fecal excretion. Without sufficient calcium, the body’s osteoclasts and osteoblasts remain inactive, which hinders proper bone turnover.⁷

The decrease in acidity leads to calcium malabsorption and increases fracture risk long- term.⁸ Khalili and colleagues surveyed 80,000 postmenopausal women to measure the incidence of hip fracture in women taking PPIs. The study found that there was a 35% increase in risk of hip fracture among women who regularly used PPIs for at least 2 years (age-adjusted hazard ratio [HR] 1.35; 95% confidence interval [CI], 1.13 -1.62). Adjusted HRs for 4-year and 6- to 8-year use of a PPI was 1.42 (95% CI, 1.05-1.93) and 1.55 (95% CI, 1.03-2.32), respectively, indicating that the longer women were on PPI therapy, the higher the risk of hip fracture. The study also evaluated the time since stopping PPI and the risk of hip fracture. Women who stopped PPI use more than 2 years prior had a similar risk to that of women who never used a PPI, indicating that the effect was reversible.⁹

Magnesium

Magnesium is an important intracellular ion that has a number of key functions in metabolism and ion transport in the human body. Once ingested, magnesium is absorbed into the bloodstream from the small and large intestines via passive and active transport. Transient receptor potential melastatin 6 (TRPM6) is one of the essential proteins that serve as a transporter for magnesium.¹⁰ The high affinity for magnesium of these transporters allows them to maintain adequate levels of magnesium in the blood. In states of low magnesium (hypomagnesemia), the body is at risk for many AEs including seizures, arrhythmias, tetany, and hypotension.¹¹

Proton pump inhibitors have been linked to hypomagnesemia, and recent evaluation has clarified a potential mechanism.¹² TRPM6 activity is increased in an acidic environment. When a PPI increases the pH of the stomach, TRPM6 and magnesium levels decrease.¹² Luk and colleagues identified 66,102 subjects experiencing AEs while taking a PPI. Hypomagnesemia had a prevalence rate of 1% in these patients. According to the researchers, PPIs were associated with hypomagnesemia and that pantoprazole had the highest incidence among all other PPIs studied (OR, 4.3; 95% CI, 3.3 – 5.7; P < .001).¹³

Vitamin B₁₂

In recent years, vitamin B₁₂ has been the subject of many studies. An area of concern is vitamin B₁₂’s neurologic effect, as it has been successfully demonstrated that vitamin B₁₂ is essential for proper cognitive function.¹⁴ Some data suggest that degeneration is present in parts of the spinal column in patients with cognitive decline or neurologic problems. These lesions are due to improper myelin formation and are specific to vitamin B₁₂ deficiency.¹⁵ In 2013 the CDC published the Healthy Brain Initiative, which stated cognitive impairment can be caused by vitamin B₁₂ deficiency.¹⁶

Similar to calcium, vitamin B₁₂ needs an acidic environment to be digested and absorbed.¹⁷ Vitamin B₁₂ is released from food proteins via gastric acid and pepsin. Once free, the vitamin B₁₂ pairs with R-binders secreted in the stomach. Pancreatic enzymes then degrade this complex into a form that can be absorbed into circulation by the intestine. Given that PPIs reduce the acidity of the stomach, they also reduce the body’s ability to release vitamin B₁₂ from food proteins and be paired with the R-binders.¹⁸

In 2013, Lam and colleagues evaluated the association between vitamin B₁₂ deficiency and the use of PPIs and H₂RAs. An extensive evaluation was performed on 25,956 patients with a diagnosis of vitamin B₁₂ deficiency and 184,199 patients without. About 12% of patients with vitamin B₁₂ deficiency had received more than a 2-year supply of a PPI, whereas only 7.2% of the patients without vitamin B₁₂ deficiency received a 2-year supply of a PPI. Four point 3 percent of patients with vitamin B₁₂ deficiency received more than a 2-year supply of an H₂RA. Only 3.2% of patients without vitamin B₁₂ deficiency received more than a 2-year supply of H₂RA. The study concluded that a 2-year or greater history of PPI (OR, 1.65; 95% CI, 1.58-1.73) or H₂RA (OR, 1.25; 95% CI, 1.17-1.34) use was associated with vitamin B₁₂ deficiency.¹⁹

PPIs and Infections

Clostridium difficile-associated disease

Nationwide CDAD has become a prevalent infection nationwide. In 2011, C difficile caused nearly 500,000 infections and was associated with 29,000 deaths in the U.S.²⁰ One study stated that C difficile is the third most common cause of infectious diarrhea in people aged >75 years.²¹

C difficile is part of the body’s normal flora in the large intestine. It grows and colonizes in an environment of low acidity. Therefore, in the stomach, where the pH is relatively low, C difficile is unable to colonize.²² When a PPI is introduced, the increased gastric pH increases the risk for CDAD.

Dial and colleagues conducted a multicenter case control study to determine whether gastric acid suppression increases the risk of CDAD. Compared with patients who did not take a gastric acid suppressant, those taking a PPI had a 2.9-fold increase in developing CDAD (95% CI, 2.4-3.4). Comparatively, H₂RAs had a 2.0-fold increase for CDAD (95% CI, 1.6 to 2.7). These results correlated with the fact that PPIs have a greater impact on gastric pH than do H₂RAs.²³

Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) has become a growing concern in the U.S. According to the Infectious Disease Society of America (IDSA) and American Thoracic clinical consensus guidelines, CAP remains one of the top reasons for hospitalizations in the U.S., and about 10% of patients admitted to the hospital for CAP end up in the intensive care unit (ICU).²⁴ In the past, PPIs have been linked to patients’ predisposal for developingCAP.²⁵ Although controversial, available evidence suggests a direct association. In 2008 Sarker and colleagues theorized a mechanism that the acid reduction of the gastric lumen allows for increased bacterial colonization in the upper part of the GI tract.²⁶ Since the acidity of the stomach serves as a defense mechanism against many ingested bacteria, many pathogens will be able to survive in the more basic environment.²⁵

Sarkar and colleagues went on to evaluate 80,000 cases over 15 years. The objective was to examine the association between PPI use and the date of diagnosis of the CAP infection, known as the index date. The study demonstrated that PPI use was not associated with increased CAP risk in the long-term (adjusted odds ratio (OR), 1.02; 95% CI, 0.97-1.08). The study did find a strong increase in the risk of CAP if a PPI was started within 2 days (adjusted OR, 6.53; 95% CI, 3.95-10.80), 7 days (adjusted OR, 3.79; 95% CI, 2.66-5.42), and 14 days (adjusted OR, 3.21; 95% CI, 2.46-4.18) of the index date.²⁶

Four years later, de Jagar and colleagues examined the differences in microbial etiology in CAP patients with and without an active PPI. Over a 4-year study period, 463 individuals were selected with clinical suspicion of CAP. The microbial etiology could be determined in 70% of those patients. The remaining 30% were excluded due to an alternative diagnosis. One of the most likely pathogens to cause a CAP infection is Streptococcus pneumoniae (S pneumonia).²⁷ Patients prescribed a PPI were significantly more likely to be infected with S pneumoniae than those not prescribed a PPI (28% vs 11%). The study concluded that the risk of S pneumoniae in patients taking a PPI was 2.23 times more likely (95% CI, 1.28-3.75).²⁸

Dementia

In 2040, it is estimated that more than 80 million people will have from dementia.²⁹ This is expected to become a large fiscal burden on the health care system. In 2010, about $604 billion was spent on therapy for dementia worldwide.³⁰ Although no cure for dementia exists, it is more feasible than in previous years to prevent its occurrence. However, many medications, including PPIs, are associated with the development of dementia; therefore, it is important to minimize their use when possible.

As noted earlier vitamin B₁₂ deficiency may lead to cognitive decline. Due to the malabsorption of vitamin B₁₂ that results from PPI use, it is hypothesized that PPIs may be associated with incidence of dementia. Badiola and colleagues discovered that in the brains of mice given a PPI, levels of β-amyloid increased significantly affecting enzymes responsible for cognition.³¹ In a February 2016, JAMA article, researchers conducted a prospective cohort study evaluating 73,679 patients aged ≥75 years with no dementia at baseline. They went on to assess regular use of a PPI, defined as at least 1 PPI prescription every 3 months, and the incidence of dementia. Patients with regular use of a PPI (≥ 1 PPI prescription every 3 months) had a 44% increase risk of incident dementia (HR, 1.44; 95% CI, 1.36-1.52; P < .001).³ Therefore, it is theorized that avoiding PPI use in the elderly may prevent the development of dementia.

Chronic Kidney Disease

The prevalence of CKD has drastically increased in recent decades. It is estimated that up to 13% of people in the U.S. are affected by CKD.³² Some studies suggest that dosing errors occur at much higher rates in patients with declined glomerular filtration rate (GFR).³³ The correct utilization use of medications becomes especially pertinent to this population. Several studies have already linked PPI use to acute interstitial nephritis (AIN) and acute kidney injury (AKI).^34-36

Lazarus and colleagues evaluated the association between PPI use and the incidence of CKD. Their analysis was performed in a long-term running population-based cohort and replicated in a separate health care system. In the running cohort, patients receiving a PPI had a 1.45-fold greater chance of developing CKD (95% CI, 1.11-1.90; P = .006). In that same cohort, patients on a PPI had a 1.72-fold increase risk of AKI (95% CI, 1.28-2.30; P < .001).⁴ Similar outcomes were seen in the replicated cohort. However, the replicated cohort did observe that twice daily dosing of a PPI (adjusted HR, 1.46; CI, 1.28-1.67; P < .001) had a stronger association with CKD than once- daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21; P < .001). H₂RAs exhibited no association with CKD in the running cohort (HR, 1.15; 97% CI, 0.98-1.36; P = .10) or the replication cohort (HR, 0.93; 95% CI, 0.88-0.99; P = .03).⁴

Clinical PPI Recommendations

There are several FDA-approved and unapproved indications that warrant PPI therapy. Proton pump inhibitor indications include gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), Helicobacter pylori, and ulcers associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

GERD Recommendations

Optimal dosing and duration is important with all medications to maximize efficacy and minimize toxicity. In the case of PPIs, dosing and duration are of particularly concern due to the aforementioned AEs. Table illustrates manufacturer-recommended dosing and duration for the most commonly prescribed PPIs. Although these dosing regimens are based on clinical studies, PPIs are commonly prescribed at higher doses and for longer durations. By extending the duration of therapy, the risk of potential long-term AEs increases dramatically. If durations are limited to the recommended window, risk of AEs can be reduced.

Alternative Therapies

There are several strategies that exist to limit the use of PPIs, including lifestyle modifications to prevent GERD, supplementation of an alternative agent to prevent high doses of the PPI, or discontinuing PPI therapy all together. Lifestyle modifications provide additional benefit as monotherapy or to supplement a pharmacologic regimen.

The American Journal of Gastroenterology promoted lifestyle modifications that include:

• Weight loss for patients with GERD who are overweight and had a recent weight gain;
• Elevation of the head of the bed (if nighttime symptoms present);
• Elimination of dietary triggers;
• Fatty foods, caffeine, chocolate, spicy food, food with high fat content, carbonated beverages, and peppermint;
• Avoiding tight fitting garments to prevent increase in gastric pressure;
• Promote salivation through oral lozenges or chewing gum to neutralize refluxed acid;
• Avoidance of tobacco and alcohol; and
• Abdominal breathing exercise to strengthen the barrier of the lower esophageal sphincter.³⁷

The above modifications may reduce the need for pharmacologic therapy, thereby reducing possible of long-term AEs.

If lifestyle modifications alone are not enough, it is reasonable to use a H₂RA for acute symptom relief or reduce high doses and frequencies of a PPI. H₂RAs are well studied and effective in the management of GERD. According to the American College of Gastroenterology 2013 clinical practice guidelines, H₂RAs can serve as an effective maintenance medication to relieve heartburn in patients without erosive disease. The guideline also states that a bedtime H₂RA can be used to supplement a once- daily daytime PPI if nighttime reflux exists. This can eliminate the need to exceed manufacturer-recommended doses.³⁷

One of the final challenges to overcome is a patient that has been maintained on chronic PPI therapy. However, caution should be exercised if choosing to discontinue a PPI. In a study by Niklesson and colleagues, after a 4-week course of pantoprazole given to healthy volunteers, those patients with no preexisting symptoms developed dyspeptic symptoms of GERD, such as heartburn, indigestion, and stomach discomfort. This correlation suggests that a rebound hypersecretion occurs after prolonged suppression of the proton pump, and therefore a gradual taper should be used.³⁸ Although no definitive national recommendations on how to taper a patient off of a PPI exist, one suggestion is a 2- to 3-week taper by using a half-dose once daily or full dose on alternate days.³⁹ This strategy has exhibited moderate success rates when used. Oral and written education on symptom management and the administration of H₂RAs for infrequent breakthrough symptoms supplemented the reduction of the PPI.

Conclusion

Proton pump inhibitors have become a popular and effective drug class for a multitude of indications. However, it is crucial to recognize the risk of long-term use. It is important to properly assess the need for a PPI and to use appropriate dosing and duration, since prolonged durations and doses above the manufacturer’s recommendations is a primary contributor to long-term consequences. Both package inserts and clinical guidelines serve as valuable resources to help balance the risks and benefits of this medication class and can help guide therapeutic decisions.

DNA helix
Image by Spencer Phillips

Researchers have developed an online “knowledgebase” called CIViC, an open access resource for collecting and interpreting information from scientific publications on cancer genetics.

“CIViC” stands for Clinical Interpretations of Variants in Cancer, and the researchers liken it to a Wikipedia of cancer genetics.

Anyone can create an account and contribute information. That information is then curated by editors and moderators who are considered experts in the field.

The researchers described the resource in Nature Genetics.

“It’s relatively easy now to sequence the DNA of tumors—to gather the raw information—but there’s a big interpretation problem,” said study author Obi L. Griffith, PhD, of Washington University School of Medicine in St Louis, Missouri.

“What do these hundreds or thousands of mutations mean for this patient? There are a lot of studies being done to answer these questions. But oncologists trying to interpret the raw data are faced with an overwhelming task of plumbing the literature, reading papers, trying to understand what the latest studies tell them about these mutations and how they may or may not be important.”

The CIViC knowledgebase is an attempt to solve this problem. The researchers said this is one of many efforts to collect and interpret such information, but, to their knowledge, CIViC is the only one that is entirely open access. Anyone is free to contribute and use the content as well as the source code.

“We are committed to keeping this resource open and available to anyone who wants to contribute or make use of the information,” said Malachi Griffith, PhD, of Washington University School of Medicine.

“We would like it to be a community exercise and public resource. The information is in the public domain. There are no restrictions on its use, academic or commercial.”

Though anyone can submit a new piece of information or suggest edits to existing data, at least 2 independent contributors must agree that the new information should be incorporated, and 1 of those users must be an “expert editor.”

Expert editors are not permitted to approve their own submissions. Information on the CIViC website provides details about how new users may be promoted to expert editors and administrators.

To date, the site has seen over 17,500 users from academic institutions, governmental organizations, and commercial entities around the world.

Since CIViC’s launch, 59 users have volunteered their time to contribute their knowledge to CIViC, including descriptions of the clinical relevance of 732 mutations from 285 genes for 203 types of cancer, all gleaned from reviewing 1090 scientific and medical publications.

Despite the fact that there are many groups attempting to collect and interpret genomic variants in cancer, the researchers said the sheer volume of information has resulted in relatively little overlap in data gathered so far.

“While we believe this is the only such open access knowledgebase, there are other large research centers with similar resources,” Malachi Griffith said. “We did an analysis to compare the big ones.”

“Even though we all have access to the same published literature, if you look at the overlap of the information mined by each of these resources, it’s remarkably small. We’re all approaching the same problem, and, just by chance—and probably because of the amount of information out there—we haven’t duplicated our efforts very much yet.”

Obi and Malachi Griffith said finding a way to combine these resources is the primary goal of an international group they are helping lead called the Variant Interpretation for Cancer Consortium, which is a part of the Global Alliance for Genomics and Health (GA4GH).

“We’re just scratching the surface of the potential this holds for precision medicine,” Obi Griffith said. “There’s a lot of work to do.”

DNA helix
Image by Spencer Phillips

Researchers have developed an online “knowledgebase” called CIViC, an open access resource for collecting and interpreting information from scientific publications on cancer genetics.

“CIViC” stands for Clinical Interpretations of Variants in Cancer, and the researchers liken it to a Wikipedia of cancer genetics.

Anyone can create an account and contribute information. That information is then curated by editors and moderators who are considered experts in the field.

The researchers described the resource in Nature Genetics.

“It’s relatively easy now to sequence the DNA of tumors—to gather the raw information—but there’s a big interpretation problem,” said study author Obi L. Griffith, PhD, of Washington University School of Medicine in St Louis, Missouri.

“What do these hundreds or thousands of mutations mean for this patient? There are a lot of studies being done to answer these questions. But oncologists trying to interpret the raw data are faced with an overwhelming task of plumbing the literature, reading papers, trying to understand what the latest studies tell them about these mutations and how they may or may not be important.”

The CIViC knowledgebase is an attempt to solve this problem. The researchers said this is one of many efforts to collect and interpret such information, but, to their knowledge, CIViC is the only one that is entirely open access. Anyone is free to contribute and use the content as well as the source code.

“We are committed to keeping this resource open and available to anyone who wants to contribute or make use of the information,” said Malachi Griffith, PhD, of Washington University School of Medicine.

“We would like it to be a community exercise and public resource. The information is in the public domain. There are no restrictions on its use, academic or commercial.”

Though anyone can submit a new piece of information or suggest edits to existing data, at least 2 independent contributors must agree that the new information should be incorporated, and 1 of those users must be an “expert editor.”

Expert editors are not permitted to approve their own submissions. Information on the CIViC website provides details about how new users may be promoted to expert editors and administrators.

To date, the site has seen over 17,500 users from academic institutions, governmental organizations, and commercial entities around the world.

Since CIViC’s launch, 59 users have volunteered their time to contribute their knowledge to CIViC, including descriptions of the clinical relevance of 732 mutations from 285 genes for 203 types of cancer, all gleaned from reviewing 1090 scientific and medical publications.

Despite the fact that there are many groups attempting to collect and interpret genomic variants in cancer, the researchers said the sheer volume of information has resulted in relatively little overlap in data gathered so far.

“While we believe this is the only such open access knowledgebase, there are other large research centers with similar resources,” Malachi Griffith said. “We did an analysis to compare the big ones.”

“Even though we all have access to the same published literature, if you look at the overlap of the information mined by each of these resources, it’s remarkably small. We’re all approaching the same problem, and, just by chance—and probably because of the amount of information out there—we haven’t duplicated our efforts very much yet.”

Obi and Malachi Griffith said finding a way to combine these resources is the primary goal of an international group they are helping lead called the Variant Interpretation for Cancer Consortium, which is a part of the Global Alliance for Genomics and Health (GA4GH).

“We’re just scratching the surface of the potential this holds for precision medicine,” Obi Griffith said. “There’s a lot of work to do.”

DNA helix
Image by Spencer Phillips

Researchers have developed an online “knowledgebase” called CIViC, an open access resource for collecting and interpreting information from scientific publications on cancer genetics.

“CIViC” stands for Clinical Interpretations of Variants in Cancer, and the researchers liken it to a Wikipedia of cancer genetics.

Anyone can create an account and contribute information. That information is then curated by editors and moderators who are considered experts in the field.

The researchers described the resource in Nature Genetics.

“It’s relatively easy now to sequence the DNA of tumors—to gather the raw information—but there’s a big interpretation problem,” said study author Obi L. Griffith, PhD, of Washington University School of Medicine in St Louis, Missouri.

“What do these hundreds or thousands of mutations mean for this patient? There are a lot of studies being done to answer these questions. But oncologists trying to interpret the raw data are faced with an overwhelming task of plumbing the literature, reading papers, trying to understand what the latest studies tell them about these mutations and how they may or may not be important.”

The CIViC knowledgebase is an attempt to solve this problem. The researchers said this is one of many efforts to collect and interpret such information, but, to their knowledge, CIViC is the only one that is entirely open access. Anyone is free to contribute and use the content as well as the source code.

“We are committed to keeping this resource open and available to anyone who wants to contribute or make use of the information,” said Malachi Griffith, PhD, of Washington University School of Medicine.

“We would like it to be a community exercise and public resource. The information is in the public domain. There are no restrictions on its use, academic or commercial.”

Though anyone can submit a new piece of information or suggest edits to existing data, at least 2 independent contributors must agree that the new information should be incorporated, and 1 of those users must be an “expert editor.”

Expert editors are not permitted to approve their own submissions. Information on the CIViC website provides details about how new users may be promoted to expert editors and administrators.

To date, the site has seen over 17,500 users from academic institutions, governmental organizations, and commercial entities around the world.

Since CIViC’s launch, 59 users have volunteered their time to contribute their knowledge to CIViC, including descriptions of the clinical relevance of 732 mutations from 285 genes for 203 types of cancer, all gleaned from reviewing 1090 scientific and medical publications.

Despite the fact that there are many groups attempting to collect and interpret genomic variants in cancer, the researchers said the sheer volume of information has resulted in relatively little overlap in data gathered so far.

“While we believe this is the only such open access knowledgebase, there are other large research centers with similar resources,” Malachi Griffith said. “We did an analysis to compare the big ones.”

“Even though we all have access to the same published literature, if you look at the overlap of the information mined by each of these resources, it’s remarkably small. We’re all approaching the same problem, and, just by chance—and probably because of the amount of information out there—we haven’t duplicated our efforts very much yet.”

Obi and Malachi Griffith said finding a way to combine these resources is the primary goal of an international group they are helping lead called the Variant Interpretation for Cancer Consortium, which is a part of the Global Alliance for Genomics and Health (GA4GH).

“We’re just scratching the surface of the potential this holds for precision medicine,” Obi Griffith said. “There’s a lot of work to do.”