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Pregnancy

CASE 68-9

QUESTION 1: E.F. is a 25-year-old Hispanic woman who is being treated with isoniazid 900 mg and rifampin

600 mg twice a week for pulmonary TB. She completed 2 months of therapy with isoniazid, rifampin,

pyrazinamide, and ethambutol, and began the new regimen 2 months ago. She recently became pregnant, and

her obstetrician is concerned about the possible teratogenic effects of her TB regimen. What are the risks of

TB and its treatment to the mother and the fetus? Are these drugs teratogenic?

Although concerns about the use of any medication during pregnancy always exist,

it is now recognized that untreated TB represents a far greater risk to a pregnant

woman and her fetus than the treatment.

33

,

66 TB is one of the leading nonobstetric

causes of maternal mortality.

179 The World Health Organization recommends that

treatment of TB in pregnant women should be the same as that for nonpregnant

women, with few exceptions.

179

Isoniazid, rifampin, pyrazinamide, and ethambutol

are not teratogenic in humans.

180

,

181

In the United States, pyrazinamide is not

recommended for use during pregnancy because of insufficient safety data.

33

If

pyrazinamide is not included in the initial treatment regimen, the minimal duration of

therapy is 9 months.

33 All pregnant women receiving isoniazid should also receive

pyridoxine 25 mg/day because of the possibility of peripheral neuropathy.

Streptomycin should not be used during pregnancy except as a last alternative

because it has been associated with mild-to-severe ototoxicity in the fetus.

179

Ototoxicity can occur throughout the gestational period and is not confined to the first

trimester. With the exception of streptomycin ototoxicity, the occurrence of birth

defects in women being treated for TB with the above agents is no greater than that of

healthy pregnant women.

182

,

183 Therefore, administration of antituberculosis drugs is

not an indication for termination of pregnancy.

33 Because E.F. likely became pregnant

after completing the first 2 months of therapy, she should continue her current regimen

for a total of 6 months because she received pyrazinamide as part of the initial

regimen.

MULTIDRUG-RESISTANT TUBERCULOSIS IN PREGNANCY

Little is known about the efficacy and safety of second-line drugs for the treatment of

MDR-TB during pregnancy. Two reports with small numbers of patients have

suggested that treatment is effective with no adverse effects to mother or child.

184

,

185

In a study of seven women treated for MDR-TB during pregnancy, no obstetric

complications or perinatal transmission of MDR-TB was observed.

184 Five women

were cured, one experienced treatment failure, and one stopped therapy

prematurely.

184 No evidence of drug toxicity was seen among their children exposed

to second-line drugs in utero, although one child was diagnosed with MDR-TB.

185

There are no well-controlled studies with bedaquiline in pregnancy; therefore, the

drug should only be used in pregnancy if clearly needed. More data are needed, but

pregnancy should not be a limitation to the treatment of MDR-TB.

LACTATION

When the baby is born, E.F. may breast-feed while continuing her medication. Drug

concentrations in breast milk are minimal and do not provide sufficient quantities for

the treatment or prevention of TB in the nursing infant.

33

,

66

Pediatrics

CASE 68-10

QUESTION 1: A.M., a 3-year-old African American boy, is suspected of having TB. His father has been

receiving treatment for TB for the last 2 months. A.M. has a productive cough, fever, and general malaise. His

sputum is positive for AFB, and his PPD skin test is positive (10 mm). What is the incidence of TB in children?

How should A.M. be treated?

The incidence of TB in children younger than 15 years of age has declined from

1,660 cases (2.9/100,000 population) in 1993 to 460 cases (0.8/100,000 population)

in 2014.

10 Children commonly have active TB disease as a complication of the initial

infection with M. tuberculosis, and the disease is characterized by intrathoracic

adenopathy, middle and lower lung lobe infiltrates, and the absence of cavitation on

chest radiography.

33

,

186 Because of the high risk of disseminated TB in infants and

children, treatment should be started as soon as the diagnosis of TB is suspected. In

general, regimens recommended for adults are also recommended for infants,

children, and adolescents, with the exception that ethambutol is not used routinely in

children.

33 Ethambutol is often avoided because it is difficult to assess visual acuity

in children. A.M. should be started on isoniazid 10 to 15 mg/kg/day, rifampin 10 to

20 mg/kg/day, and pyrazinamide 15 to 30 mg/kg/day.

33

,

66

,

186 Many experts prefer to

treat children with three drugs (rather than four) in the initial phase because the

bacillary population is usually lower than in an adult and it may be difficult for an

infant or child to ingest four drugs. If resistance is suspected, ethambutol 15 to 20

mg/kg/day or streptomycin 20 to 40 mg/kg/day should be added to the regimen until

susceptibility of the organism to isoniazid, rifampin, and pyrazinamide is known.

Pyridoxine is recommended for infants, children, and adolescents who are receiving

isoniazid.

33

If resistance is not suspected and drug susceptibility is confirmed, A.M. should

receive the isoniazid, rifampin, and pyrazinamide daily for 8 weeks. He can then

continue to take the isoniazid and rifampin daily or 2 to 3 times a week (DOT) for an

additional 4 months. The dosage for isoniazid and rifampin in a 2 to 3 times a week

regimen would be 20 to 30 mg/kg/dose and 10 to 20 mg/kg/dose, respectively (Table

68-3).

A.M. should be examined routinely for signs and symptoms of hepatitis. Although

antituberculosis medications are generally well tolerated in children, LFTs are

commonly 2 to 3 times the upper limit of normal during therapy. These are often

benign and transient; however, the incidence of hepatitis in children from isoniazid

with rifampin may be 4 to 6 times more common than in children receiving isoniazid

alone. Most hepatitis occurs within the first 3 months of therapy and generally is

associated with higher than recommended doses of isoniazid or rifampin.

123

,

187

Children and adolescents should be screened for risk factors for TB using a

questionnaire, and they should be skin tested with 5 TU of PPD if one or more risk

factors are present.

188

Insufficient data are available to recommend use of IGRAs in

children. Isoniazid for 9 months is recommended for treatment of latent TB in this

population.

188 Daily rifampin for 6 months is an acceptable alternative, especially in

children who cannot tolerate isoniazid or those exposed to a source case whose

isolate was isoniazid resistant.

188

Extrapulmonary Tuberculosis and Tuberculous

Meningitis

CASE 68-11

QUESTION 1: R.U. is a 64-year-old, 82-kg man who is brought to the emergency department after a 4-day

period during which

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he became progressively disoriented, febrile to 40.5°C, and obtunded. He also had severe headaches during this

time. Physical examination revealed moderate nuchal rigidity and a positive Brudzinski sign (neck resistant to

flexion). An initial diagnosis of possible meningitis was made, and a lumbar puncture ordered. The cerebrospinal

fluid (CSF) appeared turbid, and laboratory analysis revealed an elevated protein concentration of 200 mg/dL, a

decreased glucose concentration of 30 mg/dL, and a white blood cell count of 500/μL (85% lymphocytes). A

Gram stain of the spinal fluid and a sputum smear for AFB were negative, but the AFB smear of the CSF was

positive. Other laboratory tests were within normal limits. A diagnosis of tuberculous meningitis was made.

Discuss the presentation and prognosis of tuberculous meningitis. How should R.U. be treated?

Tuberculous meningitis is only one of the extrapulmonary complications of

infection with M. tuberculosis.

Successful treatment of extrapulmonary TB can usually be accomplished in 6 to 9

months with an acceptable relapse rate.

33

,

66

,

189 Some forms, such as bone or joint TB,

miliary TB, or tuberculous meningitis, may require 9 to 12 months of therapy.

33

Because specimens for culture and susceptibility testing may be difficult or

impossible to obtain from a site, response to treatment must be based on clinical and

radiographic improvement.

Tuberculous meningitis in older persons is usually caused by hematogenous

dissemination of the tubercle bacilli from a primary site, most commonly the lungs. In

its early stages, tuberculous meningitis often is confused with aseptic meningitis

because the Gram stain is negative. The most common symptoms of tuberculous

meningitis are headache, fever, restlessness, irritability, nausea, and vomiting. A

positive Brudzinski sign and neck stiffness may be present. As illustrated in R.U., the

CSF is usually turbid with increased protein and decreased glucose concentrations.

There is an increase in the CSF white blood cell count with a predominance of

lymphocytes. Culture of the CSF for M. tuberculosis may not be helpful because rates

of positivity for clinically diagnosed cases range from 25% to 70%.

190 Early

recognition and treatment are essential for a favorable outcome. Thus, empirical

treatment before receipt of confirmatory culture and susceptibility results is common

in suspected tuberculous meningitis. Multiple-drug therapy should be used because

irreversible brain damage or death can occur as soon as 2 weeks after the onset of

infection (not clinical symptoms).

190

TREATMENT

Treatment should be initiated in R.U. with daily administration of isoniazid 300 mg,

rifampin 600 mg, pyrazinamide 2,000 mg, and ethambutol 1,600 mg for the first 8

weeks.

33 After this initial phase of treatment, R.U. should receive daily isoniazid and

rifampin for an additional 7 to 10 months, although the optimal duration of therapy is

unknown.

33

In addition, because R.U. is older, pyridoxine 10 to 50 mg/day should be

given to prevent the occurrence of peripheral neuropathy from isoniazid. It should be

reiterated that rifampin can impart a red to orange color to the CSF.

Isoniazid readily penetrates into the CSF, with CSF concentrations reaching up to

100% of those in the serum. Rifampin is often included in tuberculous meningitis

regimens and may be associated with reduced morbidity and mortality; however,

even with inflammation, CSF concentrations of rifampin are only 6% to 30% of those

found in the serum. Ethambutol should be used in the highest dosage to achieve

bactericidal concentrations in the CSF because its CSF concentrations are only 10%

to 54% of those in the serum. Streptomycin penetrates into the CSF poorly even with

inflamed meninges.

191

CORTICOSTEROIDS

Corticosteroids in moderate-to-severe tuberculous meningitis appear to reduce

sequelae and prolong survival.

192 The mechanism for this benefit is likely owing to

reduction of intracranial pressure. Dexamethasone 8 to 12 mg/day (or prednisone

equivalent) for 6 to 8 weeks should be used and then tapered slowly after symptoms

subside.

192 Corticosteroids are likely indicated for R.U.

THERAPEUTIC DRUG MONITORING

The pharmacokinetics of the drugs used to treat tuberculosis are highly variable and

depend on weight, sex, genetic traits, and underlying comorbidities. Subtherapeutic

concentrations may be associated with a delayed response to therapy, increased risk

of relapse, or acquired drug resistance. Several studies measured drug concentrations

in patients with slow clinical response to TB treatment and found subtherapeutic

concentrations for isoniazid, rifampin, ethambutol, and rifabutin in a substantial

percentage of patients evaluated.

87

,

193–195

In one study, time to sputum culture

conversion was longer in patients with low serum concentrations.

195

In a prospective

observational study, 2-hour plasma concentrations were measured in 35 patients, and

plasma concentrations were below the normal ranges in 71%, 58%, 46%, and 10%

of patients for isoniazid, rifampin, ethambutol, and pyrazinamide, respectively.

196

In

addition, 45% of patients had subtherapeutic concentrations for both isoniazid and

rifampin. Treatment failure occurred significantly more frequently when

concentrations of isoniazid and rifampin were below the normal ranges (p = 0.013)

and below the median 2-hour drug concentration achieved in the study (p = 0.005).

196

In 142 patients with active TB, poor long-term outcomes were predicted by a 24-

hour area under the concentration–time curve (AUC) ≤363 mg × hour/L for

pyrazinamide, ≤13 mg × hour/L for rifampin, and ≤52 mg × hour/L for isoniazid.

197

Poor outcomes occurred in 32/78 patients with at least one drug with an AUC below

these threshold values compared to 3/64 patients without any low AUCs (odds ratio

= 14.14; 95% CI 4.08–49.1). Low rifampin and isoniazid peak concentrations and

AUCs predicted acquired drug resistance in all cases.

197

Based on these studies, therapeutic drug monitoring may be useful in patients with

poor or slow clinical response to therapy and allow for dosage adjustment to achieve

therapeutic drug concentrations. Additional patients who may benefit from

therapeutic drug monitoring include those with severe disease, diabetes, HIV

infection, renal dysfunction, and hepatic dysfunction.

198 A 2-hour postdose blood

sample can be obtained to estimate the peak concentration for most drugs, whereas a

3-hour postdose blood sample would be needed for rifabutin.

198 A second blood

sample at 6 hours postdose (7 hours for rifabutin) may also be obtained. Trough

concentrations for most agents are below the detection limit of the assays at the end

of a dosing interval and are not useful clinically.

198 Blood samples should be

collected in red-top test tubes and processed promptly because some drugs are not

stable at room temperature in blood or serum. Once the drug concentrations are

known, comparisons can be made to the normal ranges for each drug and doses

adjusted accordingly. However, normal ranges for drug concentrations have not been

studied in regard to clinical outcome, and optimal drug concentrations for clinical

and microbiologic efficacy are not known.

196 Although therapeutic drug monitoring

may provide useful information, clinicians must remember that serum concentrations

are only one factor among multiple factors affecting treatment outcomes.

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KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

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