Toxicology – Antituberculous Agents

Core Concept

Antituberculous medications have very different toxicity profiles, so poisoning should be approached agent by agent rather than as a single toxidrome.

This section focuses on:

• Ethambutol
• Cycloserine
• Capreomycin
• Para-aminosalicylic acid (PAS)

Isoniazid and rifampin are best considered separately because they have distinctive toxicology.

Modern tuberculosis therapy has also expanded to include agents such as bedaquiline, pretomanid, linezolid, and delamanid, especially in drug-resistant disease.

Major toxicities in this group include:

• Ethambutol → optic neuropathy
• Cycloserine → CNS and psychiatric toxicity, including seizures
• Capreomycin → renal, electrolyte, auditory, and vestibular toxicity
• PAS → GI, hepatic, hematologic, and hypersensitivity reactions

There is no single antidote for the entire group.

1. Ethambutol

Ethambutol inhibits mycobacterial cell-wall synthesis by interfering with arabinosyl transferases involved in arabinogalactan production.

Its most characteristic toxicity is:

Optic neuropathy

This usually develops during therapeutic exposure rather than following a single acute ingestion.

Ethambutol Optic Neuropathy

Clinical manifestations may include:

• Reduced visual acuity
• Blurred vision
• Central or cecocentral visual defects
• Impaired color discrimination
• Reduced contrast sensitivity

Classically, red-green color discrimination may be affected, but color abnormalities are not restricted to one specific pattern.

Risk Factors for Ethambutol Eye Toxicity

Risk increases with:

• Higher exposure
• Longer duration of treatment
• Renal impairment
• Older age
• Preexisting ophthalmic disease

Because ethambutol is substantially cleared by the kidneys, impaired renal function can increase systemic exposure.

Reversibility of Visual Toxicity

Visual function often improves after early recognition and discontinuation, but recovery may be:

• Slow
• Incomplete
• Occasionally poor

Permanent visual impairment can occur.

Therefore, new visual symptoms during ethambutol treatment require prompt assessment.

Ethambutol Monitoring

Patients should be educated to report:

• Blurred vision
• Reduced acuity
• Altered color perception
• New central visual disturbance

Depending on risk and treatment duration, monitoring may include:

• Visual acuity
• Color vision
• Formal ophthalmologic evaluation

Renal function should also be considered because it influences clearance.

Other Ethambutol Effects

Less characteristic adverse effects include:

• GI symptoms
• Rash
• Hyperuricemia
• Peripheral neuropathy
• Rare hematologic abnormalities
• Rare hepatic injury

The older source overemphasizes bone-marrow and liver toxicity relative to ethambutol’s defining clinical problem: optic neuropathy.

2. Cycloserine

Cycloserine is a second-line antituberculous drug that interferes with bacterial cell-wall synthesis.

Its toxicology is dominated by the central nervous system.

Important manifestations include:

• Irritability
• Headache
• Tremor
• Confusion
• Depression
• Anxiety
• Psychosis
• Seizures
• Encephalopathy
• Coma in severe poisoning

Neuropsychiatric toxicity may develop during therapeutic treatment as well as excessive exposure.

Cycloserine – Psychiatric Effects

Cycloserine is particularly notable for psychiatric adverse effects.

Possible manifestations include:

• Mood disturbance
• Anxiety
• Behavioral changes
• Hallucinations
• Psychosis
• Suicidal thoughts or behavior

New psychiatric symptoms during treatment should therefore be taken seriously and assessed clinically rather than automatically attributed to the underlying illness.

Cycloserine and Seizures

Cycloserine can interfere with pathways involving GABA, lowering the seizure threshold.

Risk increases with:

• Excessive systemic concentrations
• Renal impairment
• CNS disease
• Other proconvulsant drugs
• Alcohol use or withdrawal
• Electrolyte disturbances

Cycloserine and Renal Function

Cycloserine is substantially eliminated by the kidneys.

Therefore:

Renal impairment → reduced clearance → accumulation → greater neurotoxicity

Dose adjustment and clinical monitoring are particularly important when kidney function declines.

Cycloserine Concentrations

Unlike many poisoning scenarios, serum cycloserine concentrations can sometimes help evaluate accumulation during therapy.

However, a rigid historical concentration threshold should not replace clinical assessment.

Management should be guided by:

• Neurologic findings
• Renal function
• Exposure history
• Clinical trajectory

Cycloserine and Pyridoxine

Pyridoxine (vitamin B6) supplementation is commonly used during cycloserine therapy to reduce neurologic adverse effects.

Pyridoxine may also be considered as an adjunct in significant cycloserine neurotoxicity.

However, the evidence and role are less definitive than in isoniazid poisoning, where pyridoxine is a central antidotal treatment.

Cycloserine Seizure Treatment

For acute toxicologic seizures:

Benzodiazepines are first-line.

Persistent seizures may require:

• Additional benzodiazepines
• Phenobarbital
• Appropriate anesthetic management for refractory status epilepticus

Pyridoxine can be considered as an adjunct when cycloserine toxicity is strongly suspected.

Physostigmine – Important Correction

The historical recommendation of physostigmine for cycloserine-associated neuromuscular blockade is not standard modern toxicologic management.

Physostigmine should not be treated as a cycloserine antidote.

Severe weakness or respiratory failure is managed primarily with:

• Airway support
• Ventilation
• Correction of contributing abnormalities
• Discontinuation of the causative drug

Hemodialysis and Cycloserine

Cycloserine has pharmacokinetic characteristics that allow extracorporeal removal.

Hemodialysis may therefore be considered in severe poisoning or marked accumulation, particularly when:

• Renal failure is present
• Severe neurologic toxicity persists
• Recurrent seizures occur
• Clearance is substantially impaired

Dialysis decisions should be individualized with toxicology/nephrology input.

3. Capreomycin

Capreomycin is an older injectable antimycobacterial agent historically used particularly for resistant tuberculosis.

Its contemporary use has declined substantially as treatment strategies for drug-resistant TB have changed.

Its toxicity resembles aminoglycoside toxicity in several respects.

Major targets are:

• Kidneys
• Electrolytes
• Cochlear/vestibular system

Capreomycin Nephrotoxicity

Capreomycin can cause renal tubular injury.

Possible findings include:

• Rising creatinine
• Azotemia
• Tubular dysfunction
• Acute kidney injury

Risk increases with:

• Prolonged therapy
• Renal impairment
• Dehydration
• Other nephrotoxic drugs

Capreomycin Electrolyte Disturbances

Renal tubular effects can cause significant electrolyte losses, particularly:

• Hypokalemia
• Hypomagnesemia

Other electrolyte and acid–base disturbances can occur.

These abnormalities may contribute to:

• Weakness
• ECG abnormalities
• Dysrhythmia risk

Capreomycin Ototoxicity

Capreomycin may produce:

• Tinnitus
• Hearing loss
• Vestibular dysfunction
• Disequilibrium
• Vertigo

As with aminoglycosides, ototoxicity can sometimes be persistent or irreversible.

Capreomycin Neuromuscular Effects

Neuromuscular blockade has been reported.

Severe blockade could theoretically produce:

• Weakness
• Hypoventilation
• Respiratory failure

Management is primarily supportive, including mechanical ventilation when necessary.

4. Para-Aminosalicylic Acid – PAS

PAS is an older antituberculous medication now used mainly in selected resistant-TB regimens.

Its adverse-effect profile is dominated by:

• GI intolerance
• Hypersensitivity
• Hepatotoxicity

Acute overdose experience is limited.

PAS Gastrointestinal Toxicity

Common adverse effects include:

• Nausea
• Vomiting
• Abdominal discomfort
• Diarrhea

GI intolerance can become clinically important during prolonged treatment.

PAS Hypersensitivity

Hypersensitivity reactions may produce:

• Fever
• Rash
• Systemic symptoms

More serious immune-mediated effects have occasionally been described, including hepatic or hematologic involvement.

PAS Hepatic Toxicity

PAS may cause:

• Transaminase elevation
• Hepatitis
• Rare clinically significant hepatic dysfunction

Patients developing systemic hypersensitivity symptoms plus hepatic abnormalities require prompt assessment.

PAS Hematologic Effects

Rare abnormalities can include:

• Leukopenia
• Agranulocytosis
• Thrombocytopenia
• Hemolytic anemia

These are primarily complications of therapeutic exposure rather than the expected manifestation of a single acute ingestion.

PAS and Thyroid Function

A useful modern addition is that prolonged PAS therapy can contribute to hypothyroidism, especially when combined with other drugs that impair thyroid function.

This is mainly a chronic-treatment issue rather than acute poisoning.

Acute Oral Overdose

For several of these agents, acute single-ingestion data are limited.

The absence of extensive overdose reports does not mean toxicity is impossible, but many important complications occur through:

Repeated dosing + accumulation + organ dysfunction

rather than immediately after one ingestion.

Diagnosis

Identify the exact antituberculous agent.

Then assess the organ system characteristic of that drug:

Ethambutol → eyes

Cycloserine → CNS/psychiatric system

Capreomycin → kidney/electrolytes/hearing

PAS → GI/liver/hypersensitivity/blood

This agent-specific approach is more useful than treating them as a single toxicologic syndrome.

Laboratory Evaluation

Testing should be directed by the drug and symptoms.

Ethambutol

Consider:

• Renal function
• Ophthalmologic evaluation when visual symptoms occur
• Additional testing based on clinical presentation

Cycloserine

Consider:

• Glucose
• Electrolytes
• Renal function
• Acid–base status after severe seizures
• Drug concentration in selected circumstances

Capreomycin

Consider:

• Creatinine/BUN
• Potassium
• Magnesium
• Calcium
• Bicarbonate
• Other electrolytes
• ECG when significant electrolyte disturbance is present
• Hearing/vestibular assessment when symptomatic

PAS

Consider:

• Liver tests
• CBC when hematologic toxicity is suspected
• Electrolytes/renal function with significant GI losses

ECG

Routine continuous ECG monitoring is not necessary for every minor exposure.

It is appropriate when there is:

• Significant electrolyte abnormality
• Severe systemic illness
• Hypotension
• Altered consciousness
• Significant coingestion
• Dysrhythmia

Occult Coingestion

In an intentional overdose, evaluate for clinically important coingestants.

Acetaminophen testing is often useful because early poisoning can be clinically silent.

Additional testing should be guided by history and presentation rather than routine indiscriminate drug screening.

Initial Management

General priorities are:

Airway/breathing → circulation → identify exact drug → treat seizures → evaluate characteristic target organs → correct metabolic abnormalities

There is no universal antidote for this group.

GI Decontamination

Do not induce vomiting.

Ipecac is obsolete.

Routine gastric lavage is also obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The substance is adsorbable
• The airway is safe
• Aspiration risk is acceptable
• Expected benefit justifies treatment

Routine decontamination is unnecessary for many minor exposures.

Hypotension

If hypotension develops:

• Assess volume status
• Give appropriate isotonic crystalloid when indicated
• Correct contributing metabolic abnormalities
• Treat anaphylaxis when present
• Use vasopressor support for persistent shock

Norepinephrine is generally favored for persistent vasodilatory shock.

Trendelenburg positioning and automatic dopamine-first therapy are outdated.

Anaphylaxis

Any of these drugs can potentially cause hypersensitivity.

When true anaphylaxis occurs:

Epinephrine is first-line therapy.

Airway, oxygenation, circulation, and additional supportive treatment should follow standard anaphylaxis management.

Renal Injury

For capreomycin-associated renal toxicity:

• Stop further exposure
• Optimize volume status
• Avoid additional nephrotoxins where possible
• Monitor creatinine
• Monitor urine output
• Correct potassium and magnesium abnormalities

Renal replacement therapy is reserved for appropriate clinical indications.

Visual Toxicity

Suspected ethambutol optic neuropathy requires:

• Prompt recognition
• Discontinuation/reassessment of ethambutol therapy
• Ophthalmologic evaluation
• Review of renal function

Do not wait for profound visual loss before investigating symptoms.

Monitoring

Monitoring should match the agent.

Ethambutol

• Vision
• Renal function

Cycloserine

• Mental status
• Psychiatric symptoms
• Seizures
• Renal function

Capreomycin

• Renal function
• Potassium
• Magnesium
• Hearing
• Vestibular symptoms

PAS

• GI tolerance
• Liver function
• CBC when indicated
• Thyroid function during prolonged therapy when clinically appropriate

Observation

The historical universal 4–6-hour observation period is too simplistic.

Disposition depends on:

• Exact drug
• Route
• Amount
• Acute vs cumulative exposure
• Renal function
• Symptoms
• Laboratory abnormalities
• Coingestants
• Clinical trajectory

Several important toxicities—particularly ethambutol optic neuropathy and cumulative capreomycin toxicity—cannot be excluded by a few hours of emergency-department observation.

Admission

Hospitalization may be appropriate for:

• Seizures
• Severe altered mental status
• Psychosis with safety concerns
• Coma
• Respiratory failure
• Significant AKI
• Major electrolyte disturbances
• Severe hypersensitivity/anaphylaxis
• Significant hepatic injury
• Severe coingestion

ICU care is appropriate for refractory seizures, coma, respiratory failure, shock, or other major organ dysfunction.

Pregnancy

The old FDA pregnancy letter categories are obsolete.

Tuberculosis during pregnancy itself poses important maternal and fetal risks, so treatment decisions require balancing:

• Severity and drug susceptibility of TB
• Specific medication
• Maternal condition
• Gestational stage
• Available alternatives

Potential drug toxicity should therefore be considered within the context of maintaining effective tuberculosis treatment.

Pediatric Use – Important Correction

The historical statement that ethambutol, cycloserine, and capreomycin are simply “not recommended for pediatric use” is outdated as a blanket rule.

Modern pediatric TB treatment is based on:

• Drug susceptibility
• Disease severity
• Age
• Ability to monitor toxicity
• Contemporary TB guidelines

Ethambutol, in particular, is used in children when clinically indicated.

Safeguarding

Rigid age cutoffs for assuming neglect, abuse, or intentional poisoning are outdated.

Pediatric exposures should instead be assessed according to:

• Developmental capability
• Medication access
• Exposure circumstances
• Consistency of history
• Recurrent unexplained events
• Broader safeguarding concerns

Prognosis

Ethambutol

Visual toxicity may improve after discontinuation but can be permanent.

Cycloserine

Most acute CNS toxicity is potentially reversible with drug withdrawal and appropriate supportive treatment.

Capreomycin

Renal dysfunction may improve, whereas auditory or vestibular injury may persist.

PAS

GI, hepatic, hypersensitivity, and hematologic effects generally improve after recognition and withdrawal, although severe reactions can require prolonged care.

Important Modernization of the Older Source

• Antituberculous agents have agent-specific toxicities rather than one common poisoning syndrome.
• Ethambutol → optic neuropathy is the defining toxicity.
• Ethambutol toxicity is more likely with prolonged/high exposure and renal impairment.
• Ethambutol is used in modern pediatric TB care when clinically indicated; the historical blanket prohibition is outdated.
• Cycloserine → neuropsychiatric toxicity and seizures.
• Renal impairment increases cycloserine accumulation and CNS toxicity.
• Pyridoxine may be used as an adjunct with cycloserine but does not have the same established antidotal role as in isoniazid poisoning.
• Physostigmine is not a standard cycloserine antidote.
• Hemodialysis can enhance cycloserine elimination in selected severe poisoning.
• Capreomycin → nephrotoxicity + electrolyte wasting + ototoxicity and is now much less prominent in contemporary resistant-TB treatment.
• PAS → GI intolerance + hypersensitivity + hepatic/hematologic effects, with hypothyroidism relevant during chronic therapy.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and routine dopamine-first shock management are outdated.
• Fixed 4–6-hour observation cannot exclude delayed or cumulative toxicities.
• Historical FDA pregnancy letter categories are obsolete.

Key Points

• Ethambutol → optic neuropathy and color/central vision abnormalities.
• Cycloserine → psychiatric changes, tremor, confusion, seizures, and coma.
• Capreomycin → renal injury, hypokalemia/hypomagnesemia, and cochlear/vestibular toxicity.
• PAS → GI, hypersensitivity, hepatic, and hematologic toxicity.
• Renal dysfunction can substantially increase toxicity of renally eliminated TB medications.
• Benzodiazepines are first-line for cycloserine-associated toxicologic seizures.
• Pyridoxine may be considered as an adjunct for cycloserine neurotoxicity.
• Severe cycloserine accumulation may be amenable to hemodialysis.
• New visual symptoms during ethambutol therapy require prompt evaluation.
• There is no single antidote or universal monitoring strategy for this group.