Treatment of Active Tuberculosis- Challenges and Prospects by blindlove200


									                                           Clin Chest Med 26 (2005) 273 – 282

Treatment of Active Tuberculosis: Challenges and Prospects
                      Behzad Sahbazian, DOa, Stephen E. Weis, DOb,*
John Peter Smith Hospital, Viola Pitts/Como Community Health Clinic, 4701 Bryant Irvin Road, Fort Worth, TX 76107, USA
       Department of Medicine, University of North Texas Science Center, Texas College of Osteopathic Medicine,
                                3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA

    In the past 5 years, the Tuberculosis Trials Con-            emerged from the first studies of drug therapy of
sortium (TBTC) of the Centers for Disease Control                tuberculosis initiated in the late 1940s. These studies
and Prevention has completed several large studies               evaluated monotherapy with streptomycin and sub-
that have improved the understanding of pharmaco-                sequently para-aminosalicylic acid (PAS) [7 – 9].
therapy of tuberculosis. Insights gained from these              They demonstrated that drug resistance developed
studies have resulted in major changes in drug                   frequently in persons treated with monotherapy.
therapy of tuberculosis in HIV-infected and non-                 During 3 months of monotherapy with streptomycin,
infected individuals [1 – 5]. These advances require             92% of persons who remained culture-positive
that tuberculosis drug therapy now be individualized.            developed streptomycin resistance [3]. Resistance
Recommended treatment regimens are based on a                    also developed commonly during monotherapy with
patient’s risk profile that is determined by a combi-            PAS and was found in approximately one third of
nation of hematologic, microbiologic, clinical, and              patients during 4 months of treatment [9]. It was also
radiographic findings [6]. These studies have resulted           observed that resistance was much less common in
in substantial changes in the treatment guidelines.              persons treated with the combination of streptomycin
Although they are more complicated than the pre-                 and PAS, and that many more patients treated with
vious guidelines, they allow treatment to be refined             the two-drug regimen became bacteriologically nega-
so that it can be extended in patients at high risk for          tive with 4 months of therapy [9]. Ten percent or less
treatment failure and allow shorter, more convenient             of persons treated simultaneously with streptomycin
treatment regimens in patients who can be identified             and PAS developed streptomycin resistance [7,8]. It
as being at very low risk for failure [2]. This article          also was observed that development of resistance
reviews the basic principles of drug treatment of                was associated with a worse prognosis and with more
tuberculosis, individual pharmacologic agents, cur-              severe disease [3]. From these early observations
rent treatment recommendations, and several special              came the principle that tuberculosis treatment must
situations that clinicians are likely to encounter in            include simultaneous treatment with at least two ef-
medical practice.                                                fective drugs.
                                                                     The microbiologic basis for these early observa-
                                                                 tions was not identified until the early 1960s and
Axioms of chemotherapy of tuberculosis                           remains as important today to understand the design
                                                                 of current treatment regimens [10]. Persons with cavi-
   Effective tuberculosis drug therapy requires not              tary disease are estimated to have bacterial popu-
one but at least two effective drugs. This axiom                 lations of approximately 108 organisms in each cavity
                                                                 [10,11]. During division, Mycobacterium tubercu-
                                                                 losis bacilli mutate from drug-susceptible to drug-
    * Corresponding author.                                      resistant status spontaneously, randomly, and at a
    E-mail address: (S.E. Weis).               predictable rate [12]. The proportion of naturally oc-

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
274                                              sahbazian   &   weis

curring organisms that are resistant to antituberculosis     with drug-resistant tuberculosis is testimony that
drugs is variable, approximately 10À5 for ethambutol,        these principles are not being implemented success-
10À6 for isoniazid and streptomycin, and 10À8 for            fully [14].
rifampin [8]. The probability of a single organism               The last 50 years of tuberculosis drug treatment
mutating simultaneously and becoming resistant to            can be summarized succinctly. First, it was demon-
two drugs is the product of individual probabilities         strated that proper chemotherapy and the cooperation
of mutation. It can therefore be estimated that the          of the patient are the most important factors influenc-
likelihood of an organism having mutations simulta-          ing response to treatment [15]. Second, it has been
neously for isoniazid and rifampin is approximately          proven that the social factors such as those corrected
[(1 Â 10À6) Â (1 Â 10À8)] or (1 Â 10À14), and the            during sanatoria treatment of tuberculosis (which pro-
bacillary burden in human tuberculosis is several            vided bed rest, airy accommodations, a well-balanced
orders less than this [13]. This mutation rate is the        diet, good nursing care, and psychologic balance)
basis for the observation that successful drug ther-         have had no effect on outcome in persons prescribed
apy requires that at least two drugs be given                drug therapy and cooperating with treatment [15].
concurrently to prevent selection of drug-resistant          Third, a few new antituberculosis drugs have been
organisms. If a single drug is used for treatment,           developed. For the most part, however, progress has
selection of the resistant organisms occurs, and the         been made in learning to use available drugs more
patient rapidly becomes resistant to that drug. This         effectively, with treatment regimens becoming re-
mutation rate is also the basis for designing regimens       fined to the current treatments that are shorter, have
with an intensive initial phase that uses more medi-         fewer side effects, and are more convenient [6].
cations and a less intense continuation phase that uses
fewer medications.
    Corollaries of the treatment axiom that tubercu-
losis treatment must include simultaneous treatment          Pharmacology and toxicity of antimycobacterial
with at least two effective drugs are important for          agents
designing effective tuberculosis regimens and tu-
berculosis control programs. Because of the possi-               The current drugs approved by the Food and Drug
bility of resistance, a single drug is never added to        Administration (FDA) for the treatment of tuber-
a failing drug-treatment regimen. Optimal design of          culosis include isoniazid, pyrazinamide, rifampin,
re-treatment regimens should include at least two            rifapentine, ethambutol, cycloserine, ethionamide, ca-
medications to which the patient is naıve, and ¨             preomycin, PAS, and streptomycin. Drugs that com-
clinicians designing initial treatment regimens must         monly are recommended by expert panels for use in
consider prevailing tuberculosis-susceptibility pat-         the treatment of tuberculosis but are not FDA ap-
terns in the community where the infection probably          proved include rifabutin, the aminoglycosides includ-
was acquired. It is equally important to successful          ing amikacin, kanamycin, and the fluoroquinolones
treatment that the patient actually take the two proba-      including ciprofloxacin, moxifloxacin, and levofloxacin.
bly effective drugs. The only way to ensure that a           Of the approved drugs, isoniazid, rifampin, ethambu-
patient actually takes drug therapy as prescribed is         tol, and pyrazinamide are considered first-line anti-
direct observation of therapy. If three separate drugs       tuberculosis drugs. Rifapentine and rifabutin can also
are prescribed for a patient with tuberculosis, the          be considered first-line drugs under special condi-
patient may, for many reasons, take a single drug at         tions discussed later. The others are categorized as
a time. Short-term single-drug therapy in a person           second-line drugs, which are used when the first-line
with high bacillary burden can lead to emergence             drugs are unsuitable because of drug intolerance
of drug resistance [7 – 9]. If a patient happens to          or infection with drug-resistant tuberculosis. Addi-
be initially resistant to one drug and takes a combi-        tionally clarithromycin, amoxicillin/clavulanate, and
nation of two drugs, including the one to which he           linezolid have been used in the treatment of patients
or she is resistant, drug resistance to the second           with drug-resistant tuberculosis.
drug will emerge. Similarly, if the patient is resistant         Drug-level monitoring is not routinely an impor-
to two drugs and takes these two drugs and a single          tant aspect of treatment in a patient with active
effective drug, resistance to the third will emerge.         tuberculosis. Therapeutic drug monitoring is most
Therefore, poor adherence, inadequate prescribing,           useful when there is a direct relationship between
or both may result in the development of multidrug           serum concentrations and therapeutic response and
resistance. Although these axioms may seem self-             when serum concentrations serve as a surrogate for
evident, the growing number of persons worldwide             drug concentrations at the site of action. Therapeutic
                                       treatment of active tuberculosis                                         275

drug monitoring is also important when there is a                Peripheral neuropathy also is associated occasion-
narrow range of concentrations that are effective           ally with use of isoniazid. Neuropathy occurs more
and safe and when toxicity or lack of effectiveness         commonly among persons who have other risks
puts the patient at great risk [16,17]. Examples of         for neuropathy. Persons at increased risk of periph-
situations in which therapeutic drug monitoring is          eral neuropathy include those who are nutritionally
useful for safety include persons treated with amino-       deficient, alcoholics, diabetics, pregnant women,
glycosides and persons treated with ethambutol or           breastfeeding mothers, and patients with renal dis-
cycloserine with renal impairment.                          ease. Vitamin B6 (pyridoxine) supplements usually
                                                            are given with isoniazid to prevent development of
                                                            peripheral neuropathy [6].
Isoniazid                                                        Hypersensitivity reactions including arthralgias,
                                                            irritability, seizures, and lupuslike syndrome have
    Isoniazid is used for the treatment of both latent      also been reported in patients receiving isoniazid.
and active tuberculosis and works primarily by              Although as many as 20% of patients treated with
inhibiting cell wall synthesis. It is usually adminis-      isoniazid develop a positive antinuclear antibody test,
tered orally but has been given successfully intra-         systemic lupus rarely occurs [26].
muscularly or intravenously [6]. Isoniazid is cleared            Isoniazid has clinically important reactions with
predominantly through the liver by acetylation. A           other concomitantly used medications. Isoniazid
patient’s acetylation status and the associated differ-     can affect the levels of certain antiseizure medica-
ences in plasma isoniazid concentrations are not as-        tions, such as phenytoin and carbamazepine. Levels
sociated with isoniazid-induced liver injury [18].          of these medications must be monitored during iso-
Additionally, no association was found between              niazid therapy [6].
plasma isoniazid concentrations and isoniazid-induced
liver injury [19]. Isoniazid is distributed throughout
the body with peak concentrations occurring within          Rifamycins
1 to 2 hours after the administration of an oral dose
[20]. The usual dose for isoniazid is 3 to 5 mg/kg              The rifamycins, which include rifampin, rifabutin,
body weight/day in adults with a maximum dose               and rifapentine, work by interfering with RNA
of 300 mg/day [6].                                          synthesis, even in bacilli with minimal metabolic
    Isoniazid generally is well tolerated. Hepatic side     activity [27]. The rifamycins are variable inducers of
effects are perhaps the best known of the untoward          the cytochrome P450 system. Rifampin, rifabutin,
effects associated with isoniazid use. Less well            and rifapentine are each first-line drugs for the treat-
known is the asymptomatic elevation of liver amino-         ment of tuberculosis in different circumstances.
transferases of up to five times the upper limits of        Rifampin generally is given orally, but formulations
normal, which occurs in approximately 20% of                are available for parenteral therapy. The usual dose
patients receiving isoniazid. This asymptomatic mild        for rifampin in adults is 10 mg/kg to a maximum of
elevation of liver aminotransferases is not progres-        600 mg daily. It is distributed well throughout the
sive, is not an indication of progressive liver toxicity,   body and reaches effective concentrations in all tis-
and when asymptomatic does not require discon-              sues [6]. Rifampin is a necessary component of all
tinuation of isoniazid treatment [6]. Isoniazid-induced     short-course regimens [6].
hepatitis does occur, but recent studies indicate it is         Rifampin is generally a well-tolerated drug. The
less common than previously thought. Isoniazid-             most common side effect of rifampin use is an
induced hepatitis is estimated to occur in 0.15% of         orange discoloration of the urine, tears, and other
those starting and in 0.15% of those completing             body fluids. The change in the color of the urine or
treatment for latent tuberculosis infection [21]. The       other body fluids can be disconcerting to persons
rate of isoniazid-induced hepatitis is higher when          treated with rifampin if they are not warned. This
isoniazid is combined with rifampin [22]. It is also        discoloration has been associated with discoloration
more common in older persons, heavy alcohol                 of soft contact lenses and clothing. This staining
consumers, and persons with underlying liver disease        must be rare, however, because the author and col-
[23]. Based on a large survey, the risk of isoniazid-       leagues have treated many contact lens wearers with
induced fatal hepatitis is much lower than previously       rifampin and never have had a complaint of dis-
thought—0.001%—when patients are monitored rou-             coloration of contacts lens, even though they rou-
tinely for liver toxicity [24,25]. The risk increases       tinely warn patients of this potential side effect.
slightly in patients over the age of 35 years.              Rifampin can also cause pruritus [28]. Gastroin-
276                                             sahbazian   &   weis

testinal upset, including diarrhea, nausea, and ab-         concurrent medications must be checked for inter-
dominal pains, can occur but rarely require drug            actions with rifampin.
discontinuation and are usually self limiting [29].
Transient elevation of serum bilirubin may be ob-           Ethambutol
served during rifampin administration. Hepatitis is
more common when rifampin is administered with                  Ethambutol is used in combination with isoniazid
isoniazid [30].                                             and rifampin in the initial treatment of active tuber-
    A more serious side effect of rifampin use is an        culosis and has been proven effective in primary
influenzalike syndrome. Symptoms often mistaken             treatment of pulmonary tuberculosis [35]. Ethambutol
by patients and physicians for influenza, including         is used with isoniazid and rifampin to prevent
fevers, chills, faintness, headaches, myalgia, and ar-      selecting resistant organisms when resistance to
thralgia, occur alone or in combination. This hyper-        one of the primary drugs is present. Like isoniazid,
sensitivity syndrome seems to be immune mediated            ethambutol inhibits cell wall synthesis. It is available
and develops primarily when rifampin is given               only in the oral form. Because it is secreted through
intermittently or in larger doses than are currently        the kidneys, it can accumulate in patients with renal
recommended. It most commonly develops after 3 to           insufficiency. The usual dose for ethambutol is 15 to
6 months but can occur at any time during treatment         20 mg/kg/day or 50 mg/kg two times per week.
[31]. Among persons receiving once-weekly rifampin              Ethambutol generally is very well tolerated, but,
as part of the antituberculosis regimen, 35% to 57%         rarely, it can cause retrobulbar neuritis. This syn-
of persons who received 1200 to 1800 mg rifampin            drome first manifests as decreased red-green color
developed a flulike syndrome; the rates were 22% to         discrimination and visual acuity. Although it can
31% among those receiving 900 mg/week and 10%               result in irreversible vision loss, recognition of the
among persons taking 600 mg/week [32]. In contrast,         symptoms and prompt discontinuation of the drug
for persons who received twice-weekly rifampin, a           usually results in return of normal vision. Reducing
flulike syndrome was reported in 8% of those                the dose of ethambutol to 15 mg/kg/day can minimize
receiving 900 mg/week and in 4% of those receiving          the risk [36].
600 mg/week. Symptoms usually appear 1 to 2 hours
after administration of the drug and last up to 8 hours     Fluoroquinolones
[31,32]. The hypersensitivity syndrome can be ac-
companied by other manifestations that may be                   Levofloxacin, moxifloxacin, and gatifloxacin
severe and, rarely, life threatening. The incidence         all are active against mycobacterium tuberculosis
of individual adverse drug reactions included in            [37,38]. Although they are not approved by the
the hypersensitivity syndrome is not well described         FDA for the treatment of tuberculosis, they are
for persons treated for tuberculosis. A study of            used frequently in treating drug-resistant tubercu-
20,667 patients treated for leprosy with rifampin,          losis or when patients are intolerant of first-line
600 mg/day for 3 months, noted the following                agents [39,40]. The adult dose for levofloxacin is
incidence rates: rash (0.07%), acute renal failure          500 to 1000 mg/day orally. Moxifloxacin is admin-
(0.1%), thrombocytopenia (0.01%), and hypotension           istered at 400 mg/day. Central nervous system (CNS)
(0.01%) [33]. Rifabutin use is also associated with         concentrations of fluoroquinolones have been found
rare immune-related reactions. These reactions tend         to be around 16% to 20% of serum after admin-
to be hematologic, such as leukopenia and thrombo-          istration of a standard dose of levofloxacin [41].
cytopenia [33,34].                                          Microbial resistance to fluoroquinolones is common
    Rifampin can interact with a large number of            in the community setting; therefore it is imperative
medications because it is a potent inducer of several       that fluoroquinolones be used only when appropriate.
enzymes. Rifampin induction of hepatic enzymes can          The most common side effects reported with the use
reduce serum concentrations of oral contraceptives,         of this group of antimicrobials are gastrointestinal
resulting in pregnancy, and women relying on hor-           symptoms such as nausea, anorexia, dyspepsia, ab-
monal methods of contraception need to use addi-            dominal pain, followed by CNS disturbances (head-
tional means of contraception. Rifampin can increase        ache, dizziness, drowsiness, abnormal vision) and
the metabolism of methadone and glucocorticoids,            liver enzyme abnormalities [42]. Fluoroquinolones
resulting in narcotic withdrawal syndrome and ad-           were not developed with the expectation that they
renal insufficiency or exacerbation of the illness          would be used for months; however most experts in
being treated by glucocorticoid. The interactions of        the field of TB have reported a good safety profile
rifampin with other drugs are so extensive that all         and tolerability with long-term use. Controlled stud-
                                        treatment of active tuberculosis                                         277

ies are in progress by CDC/TBTC to look at fluo-
                                                               Box 1. Infectious Diseases Society of
roquinolones as there is a dearth of information on
                                                               America/United States Public Health
the efficacy of long-term fluoroquinolone treatment
                                                               Service rating system for treatment
(either daily or intermittently) as is required for multi-
                                                               recommendations based on quality of
drug resistant TB.
                                                                   Strength of the recommendation
    Pyrazinamide is the primary drug used in the ini-
                                                                   A. Preferred; should generally be
tial intensive phase of active tuberculosis therapy
to reduce the total length of therapy. It has a steril-
                                                                   B. Alternative; acceptable to offer
izing effect and helps eliminate potential persisters
                                                                   C. Offer when preferred or alternative
and consequently is used in the first two months of
                                                                      regimens cannot be given
intensive therapy to reduce the total length of ther-
                                                                   D. Should generally not be offered
apy [43]. It is administered orally and is first broken
                                                                   E. Should never be offered
down by the liver. The remaining metabolites are
excreted through the kidney [44]. It is more hepa-
totoxic than isoniazid; therefore, liver function tests           Quality of evidence supporting the
should be monitored. It can exacerbate gout and                recommendation
arthralgias by elevating serum uric acid levels [45].
The adult dose for pyrazinamide, based on estimated                  I. At least one properly randomized
lean body weight, is 25 mg/kg for daily oral ad-                        trial with clinical end points
ministration orally, 37.5 mg/kg for trice-weekly                    II. Clinical trials that either were not
administration, and 50 mg/kg for twice-weekly ad-                       randomized or were conducted in
ministration [6].                                                       other populations
                                                                   III. Expert opinion
                                                               From Gross PA, Barrett TL, Dellinger EP,
    Amikacin [46], kanamycin [47], and capreomycin             et al. Purpose of quality standards for in-
are three aminoglycosides that are second-line agents          fectious diseases. Infectious Diseases So-
used in treatment of patients who have resistant               ciety of America. Clin Infect Dis 1994;18:
tuberculosis. They are available for both intramus-            421; with permission.
cular and intravenous administration. All three are
administered at 15 mg/kg/day (maximum, 1.0 g/day).
Sensitivity tests have shown incomplete cross-
resistance between amikacin and capreomycin but              United States Public Health Service and the Infec-
complete cross-resistance between amikacin and               tious Diseases Society of America (Box 1) [6].
kanamycin [48]. Adverse effects most commonly                    The guidelines recommend four regimens for
associated with the use of these drugs are ototoxicity       treating persons with drug-susceptible tuberculosis
and nephrotoxicity. Patients receiving these medica-         [6]. These regimens contain recommendations for
tions should have regular audiograms, vestibular and         regimen modification under circumstances deter-
Romberg testing, and monitoring of renal function.           mined by a combination of hematologic, microbio-
                                                             logic, clinical, and radiographic findings [6]. Each
                                                             regimen has an initial intensive phase of 2 months
Treatment guidelines                                         followed by several options for the continuation
                                                             phase of 4 or 7 months’ duration. These regimens,
    Tuberculosis treatment guidelines for the United         together with the number of doses specified by the
States have been prepared by and endorsed by the             regimen, are described in Table 1. The initial phases
American Thoracic Society, the Infectious Diseases           are denoted by a number (1, 2, 3, or 4), and the con-
Society of America, and the Centers for Disease              tinuation phases associated with the initial phase are
Control and Prevention. These regimens are, for the          denoted by the number of the initial phase plus a letter
most part, evidence based. These guidelines rate             designation for the continuation phase (a, b, or c).
treatments according to the strength of the evidence             The continuation phase can be given daily, two
supporting their use, using a system developed by the        times per week, or three times per week with iso-
Table 1
Drug regimens for culture-positive pulmonary tuberculosis caused by drug-susceptible organisms
Initial phase                                                        Continuation phase                                                        Range of total doses      (evidence)b
Regimen         Drugs    Interval and dosesc (minimal duration)      Regimen       Drugs         Interval and dosesc,d (minimal duration)      (minimal duration)        HIVÀ       HIV+
1               INH      7 d/wk for 56 doses (8 wk) or 5 d/wk        1a            INH/RIF       7 d/wk for 128 doses (18 wk) or               182 – 130 (26 wk)         A (I)      A (II)
                RIF      for 40 doses (8 wk)e                                                    5 d/wk for 90 doses (18 wk)c
                PZA                                                  1b            INH/RIF       2Â/wk for 36 doses (18 wk)                     92 – 76   (26   wk)      A (I)      A (II)f
                EMB                                                  1cg           INH/RPT       1Â/wk for 18 doses (18 wk)                     74 – 68   (26   wk)      B (I)      E (I)
2               INH      7 d/wk for 14 doses (2 wk), then            2a            INH/RIF       2Â/wk for 36 doses (18 wk)                     62 – 68   (26   wk)      A (II)     B (II)f
                RIF      2Â/wk for 12 doses (6 wk) or 5 d/wk         2bg           INH/RPT       1Â/wk for 18 doses (18 wk)                     44 – 40   (26   wk)      B (I)      E (I)
                PZA      for 10 doses (2 wk)e then 2Â/wk for
                EMB      12 doses (8 wk)

3               INH      3Â/wk for 24 doses (8 wk)                   3a            INH/RIF       3Â/wk for 54 doses (18 wk)                     78 (26 wk)               B (I)      B (II)

4               INH      7 d/wk for 56 doses (8 wk) or 5 d/wk        4a            INH/RIF       7 d/wk for 217 doses (31 wk) or               273 – 195 (39 wk)         C (I)      C (II)

                RIF      for 40 doses (8 wk)e                                                    5 d/wk for 156 doses (31 wk)c
                EMB                                                  4b            INH/RIF       2Â/wk for 62 doses (31 wk)                    118 – 102 (39 wk)         C (I)      C (II)
Abbreviations: EMB, Ethambutol; HIVÀ, HIV-negative; HIV+, HIV-positive; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT, rifapentine.
      Definitions of evidence ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given.
      Definitions of evidence ratings: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion.
      When directly observed therapy is used, drugs may be given 5 d/wk and the necessary number of doses adjuated accordingly. Although there are no studies that compare five
with seven daily doses, extensive experience indicates this would be an effective practice.
      Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 wk; either 217 doses [7Â/wk] or 62 doses
[2Â/wk]) continuation phase.
      Five d/wk administration is always given by DOT. Rating for 5 d/wk regimens is A III.
      Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/ml.
      Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation
on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from 2-month specimen, treatment should be extended an extra 3 months.
From American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;
                                       treatment of active tuberculosis                                       279

niazid and rifampin. It can also be given, more con-       therapy group. There was no demonstrable improve-
veniently for patients and staff, once weekly using        ment in the broader prespecified combined end points
isoniazid and rifapentine in patients with tuberculo-      of death or severe disability after 9 months [52].
sis without cavitation on the chest radiograph. This           There have been many reports of an increased risk
group is estimated to represent 40% of persons with        of tuberculosis in patients receiving tumor necrosis
tuberculosis in the United States [3]. Persons who         factor- alpha (TNF-a) antagonists [53,54]. These
have cavitation on the initial or follow-up chest          agents, which include infliximab, etanercept, and
radiograph or who are culture positive at the end          adalimumab, are used for the treatment of an ex-
of initial phase of therapy (usually completed after       panding group of diseases and work by blocking
2 months) have an unacceptably high risk of treat-         TNF-a; an inflammatory cytokine. TNF-a is ex-
ment failure [3,6]. For these patients, the continuation   pressed by activating macrophages, T cells, and other
phase should be extended for an additional 3 months        immune cells and is an important part of the host
[6]. It is critically important to have sputum cultures    response against M. tuberculosis and other intra-
at the time of completion of the initial phase of treat-   cellular organisms. Current expert opinion on this
ment to identify patients at increased risk of relapse.    emerging problem in tuberculosis treatment is that
The treatment of tuberculosis in persons with HIV          the TNF-a antagonist should be discontinued if
is discussed elsewhere in this issue.                      tuberculosis develops during TNF-a antagonist ther-
    Treatment of tuberculosis may be delayed for           apy. The optimal time for resuming TNF-a antagonist
many reasons. The current treatment guidelines de-         therapy is undetermined. It is recommended that
fined completion of adequate therapy by the number         TNF-a antagonist therapy be withheld at least until
of doses ingested as well as by the duration of            treatment with the tuberculosis regimen has been
treatment administration [6]. The minimum goal for         started, and the patient’s condition has improved [54].
adequate therapy is delivery of the full number of             Tuberculosis occurring in pregnancy is a danger to
doses in no more than 150% of the expected delivery        the pregnant woman and her child, and treatment
duration [6].                                              should not be delayed because of the pregnancy. In-
                                                           fants born to women with untreated tuberculosis may
Special situations                                         be of lower birth weight than those born to women
                                                           without tuberculosis and can acquire congenital
    Central nervous system tuberculosis is one of the      tuberculosis [55 – 57]. Of the first-line medications,
most devastating presentations of human tuberculo-         pyrazinamide is not recommended for general use in
sis. Disability and death occur despite antitubercu-       pregnant women in the United States because of
losis therapy [49]. The best antimicrobial agents for      insufficient data to determine safety. Aminoglyco-
the treatment of central nervous system tuberculosis       sides should not be used to treat tuberculosis in preg-
have not been validated by well-designed, random-          nancy, because they are associated with birth defects
ized, clinical trials. Isoniazid and pyrazinamide pene-    [6]. There is little information about the safety of
trate the meninges in all stages of inflammation.          second-line antituberculosis drugs during pregnancy.
Rifampin, ethambutol, and aminoglycosides pene-            The recommended initial treatment regimen in preg-
trate the blood – brain barrier in the presence of men-    nancy should consist of isoniazid, rifampin, and
ingeal inflammation but poorly in its absence. The         ethambutol [6]. If the organism is confirmed to be
use of glucocorticoids in an attempt to reduce mor-        susceptible to isoniazid and rifampin, the ethambutol
tality and morbidity has been controversial [50].          may be discontinued and isoniazid and rifampin con-
Recently, a large trial of dexamethasone adjunct           tinued for a minimum of 9 months [6]. It is recom-
therapy for persons 14 years of age and older with         mended that pregnant women receiving isoniazid also
tuberculous meningitis has clarified the role of glu-      be given pyridoxine (25 mg/day) [6]. Breastfeeding
cocorticoids [51]. Dexamethasone treatment was             should not be discouraged for women being treated
started as soon as possible after starting antituber-      with first-line agents, because the small concentra-
culosis treatment. Patients were stratified by Glasgow     tions of these drugs in breast milk do not produce
Coma Scale and given intravenous dexamethasone             toxic effects in the nursing infant [58].
for 4 weeks for severe disease and for 2 weeks for             Renal insufficiency increases the risk for devel-
mild disease. Subsequently, all patients were given        oping tuberculosis, and treatment of the two con-
tapering doses of dexamethasone orally for an addi-        ditions concurrently is a complex and common
tional 4 weeks. Dexamethasone adjunctive treatment         situation. Isoniazid and rifampin are metabolized in
improved survival. Adverse and severe adverse events       the liver, and dosages need not be changed in persons
were reduced significantly in the dexamethasone-           with chronic renal failure [59 – 61]. Metabolites of
280                                              sahbazian   &   weis

pyrazinamide are excreted renally and can accumu-            mens in patients who can be identified as being at
late in patients with renal insufficiency [61]. Approxi-     very low risk for failure [2].
mately 80% of ethambutol is cleared by the kidneys,
so ethambutol may accumulate in patients with renal
insufficiency [59,61]. Reducing the dosage may avoid         Acknowledgments
toxicity, but the peak serum concentrations achieved
may be too low to be effective. Therefore increasing             The authors acknowledge Thaddeus Miller’s work
the dosing interval is recommended [60]. For patients        in editing this article.
undergoing hemodialysis, administering all drugs for
tuberculosis after dialysis is a way to facilitate di-
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