DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1566 Therapy of MAC Pulmonary Infection
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
M. intracellulare often infects immunocompetent patients. The first
decision after isolating MAC from pulmonary specimens is to determine
whether disease is actually present or if the organism is merely
part of environmental contamination. Criteria in favor of therapy
includes bacteriological evidence, which consists of positive cultures
from at least two sputums, or one positive culture from bronchoalveolar
lavage or pulmonary biopsy with a positive culture or
histopathological features, and clinical evidence of infection, and
radiological evidence of infection such as pulmonary cavitation,
nodular lesions, and/or bronchiectasis (Griffith et al., 2007).
In newly diagnosed patients with MAC pneumonia, triple drug
therapy is recommended. These include a rifamycin, ethambutol, and
a macrolide (Griffith et al., 2007; Kasperbauer and Daley, 2008). For
the macrolides, either oral clarithromycin or azithromycin may be
used. Rifampin is often the rifamycin of choice. Clarithromycin, 1000
mg, or azithromycin, 500 mg, are combined with ethambutol, 25
mg/kg, and rifampin, 600 mg, and administered three times a week
for nodular and bronchiectatic disease. Therapy is continued for 12
months after the last negative culture. The same drugs are administered
for patients with cavitary disease, but the dosing regimens are
azithromycin 250 mg, ethambutol 15 mg/kg, and rifampin 600 mg.
Parenteral streptomycin or amikacin at 15 mg/kg are recommended
as a fourth drug. The effect of the aminoglycosides on clinical outcomes
is unclear. Duration of therapy is as for nodular disease. In
advanced pulmonary disease or during re-treatment, rifabutin 300 mg
daily may replace rifampin. Because clarithromycin susceptibility
correlates with outcome, risk of failure is high when high clarithromycin
MICs are documented. Patients at risk for failure also
include those with cavitary disease, presumably due to higher bacillary
load. Even with these therapies, long-term success is still fairly
limited. Only half of patients have successful outcomes as defined by
both culture conversion and clinical outcomes.
Therapy for Disseminated
M. Avium Complex
Disseminated MAC disease is caused by M. avium in
95% of patients. This is a disease of the immunocompromised
patient, especially with reduced cell-mediated
immunity. MAC usually occurs in patients whose CD4
cell count is <50/mm 3 . Patients at risk for infection are
those who have had other opportunistic infections, are
colonized with MAC, or have an HIV RNA burden
>5 log copies/mm 3 .
The symptoms and laboratory findings of disseminated disease
are nonspecific and include fever, night sweats, weight loss,
elevated serum alkaline phosphates, and anemia at the time of diagnosis.
However, when disease occurs in patients already on antiretroviral
therapy, it may manifest as a focal disease of the lymph nodes,
osteomyelitis, pneumonitis, pericarditis, skin or soft-tissue
abscesses, genital ulcers, or CNS infection (DHHS Panel, 2008). In
addition to a compatible clinical picture, isolation of MAC from cultures
of blood, lymph node, bone marrow, or other normally sterile
tissue or body fluids is required for diagnosis.
Prophylactic Therapy. The goals of prophylactic therapy are to prevent
the development of disease during the time when a patient’s CD4
count is low. Monotherapy with either oral azithromycin 1200 mg
once a week or clarithromycin 500 mg twice a day is started when
patients present with a CD4 count <50/mm 3 (DHHS Panel, 2008).
For patients intolerant to macrolides, rifabutin 300 mg a day is administered.
Once the CD4 count is >100 per mm 3 for ≥3 months, MAC
prophylaxis should be discontinued.
Definitive and Suppressive Therapy. In patients with disease due
to MAC, the goals of therapy include suppression of symptoms and
conversion to negative blood cultures. The infection itself is not completely
eradicated until immune reconstitution. Therapy is divided
into initial therapy and chronic suppressive therapy. Recommended
therapy consists of a combination of clarithromycin 500 mg twice a
day with ethambutol 15 mg/kg daily, administered orally (DHHS
Panel, 2008). Azithromycin 500-600 mg daily is an acceptable alternative
to clarithromycin, especially in those patients in whom
clarithromycin would adversely interact with other drugs. The addition
of rifabutin 300 mg a day may improve outcomes. Mortality in
disseminated MAC is high in patients with either a CD4 cell count
<50/mm 3 or a MAC burden of >2 log 10
CFU/mm 3 of blood, or in the
absence of effective antiretroviral therapy. In these patients, a fourth
drug may be added, based on susceptibility testing. Potential fourth
agents include amikacin, 10-15 mg/kg intravenously daily; streptomycin,
1 g intravenously or intramuscularly daily; ciprofloxacin,
500-750 mg orally twice daily; levofloxacin, 500 mg orally daily;
or moxifloxacin, 400g orally daily. Patients should be continued on
suppressive therapy until all three of the following criteria are met:
• therapy duration of at least 12 months
• CD4 count >100/mm 3 for at least 6 months
• asymptomatic for MAC infection
PRINCIPLES OF ANTI-LEPROSY
THERAPY
The global prevalence of leprosy has markedly
declined, largely due to the global initiative of the WHO
to eliminate leprosy (Hansen’s disease) as a public
health problem by providing multidrug therapy
(rifampin, clofazimine, and dapsone) free of charge.
Prevalence of the disease has dropped by ~90% since
1985. Nevertheless, there are pockets of disease around
the world, especially in Africa, Asia, and South
America. In the U.S., <200 new cases were reported in
2005, mainly among immigrants.
Four major clinical types of leprosy impact therapy. At one
end of the spectrum is tuberculoid leprosy, also termed paucibacillary
leprosy because the bacterial burden is low and M. leprae is
rarely found in smears. On the other end of the spectrum is the
lepromatous form of the disease (Levis and Ernst, 2005). This is
characterized by a disseminated infection and a high bacillary burden.
Two major intermediate forms of the disease are recognized:
borderline (dimorphous) tuberculoid disease, which has features
of both tuberculoid and lepromatous leprosy, and indeterminate