What are the considerations for selecting antitubercular drugs in critically ill patients requiring Intensive Care Unit (ICU) care, particularly those with impaired renal function, hepatic dysfunction, or potential drug interactions?

Antitubercular Drug Management in the ICU

Core Principle: Adjust Dosing Intervals, Not Doses

In critically ill ICU patients with renal impairment (CrCl <30 mL/min), increase the dosing interval to three times weekly for pyrazinamide and ethambutol rather than reducing the dose, as dose reduction compromises peak concentrations and treatment efficacy. 1

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Initial Assessment Before Starting Therapy

Mandatory Baseline Testing

• Calculate actual creatinine clearance using 24-hour urine collection rather than relying on serum creatinine alone, especially in elderly patients or those with reduced muscle mass, as serum creatinine significantly underestimates renal impairment 2
• Obtain baseline liver function tests (AST, ALT, bilirubin) 3
• Perform visual acuity testing and color discrimination assessment 4
• Establish baseline audiogram and vestibular testing if injectable agents are considered 5
• Screen for hepatitis B and C in high-risk patients (injection drug users, HIV-positive patients) 3

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Drug-Specific Dosing in Renal Impairment (CrCl <30 mL/min or Hemodialysis)

No Adjustment Required (Hepatically Metabolized)

• Isoniazid: 300 mg once daily OR 900 mg three times weekly 1
• Rifampin: 600 mg once daily OR 600 mg three times weekly 1
• Both drugs are hepatically metabolized and maintain standard dosing in renal failure 1

Frequency Adjustment Required (Renally Cleared)

• Pyrazinamide: 25-35 mg/kg three times weekly (NOT daily) 1

  • Although hepatically metabolized, metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) accumulate in renal insufficiency 1
  • PZA is significantly cleared by hemodialysis 1

• Ethambutol: 20-25 mg/kg three times weekly (NOT daily) 1, 4

  • Approximately 80% undergoes renal clearance and will accumulate with daily dosing 1
  • Partially cleared by hemodialysis 1

Second-Line Agents

• Levofloxacin: 750-1000 mg three times weekly (NOT daily) due to significant renal clearance 1
• Moxifloxacin: 400 mg once daily (no adjustment needed) 1
• Injectable agents (streptomycin, amikacin, kanamycin, capreomycin): 15 mg/kg 2-3 times weekly (NOT daily) 1

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Critical Timing: Hemodialysis Patients

Administer all antitubercular medications immediately after hemodialysis on dialysis days to prevent premature drug clearance and facilitate directly observed therapy 1

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Hepatic Impairment Management

For Advanced Liver Disease or Baseline ALT >3× Upper Limit of Normal

• Omit pyrazinamide and use isoniazid, rifampin, and ethambutol for 2 months, followed by 7 months of isoniazid and rifampin (total 9 months) 3
• This avoids the most hepatotoxic agent while maintaining efficacy 3

For Patients Who Cannot Tolerate Isoniazid

• Use rifampin, ethambutol, and a fluoroquinolone (with or without an injectable agent) for 12-18 months 3
• This eliminates both isoniazid and pyrazinamide, the two most hepatotoxic first-line agents 3

Monitoring During Treatment

• Stop all hepatotoxic drugs immediately if bilirubin rises at any level, regardless of transaminase values 3
• For asymptomatic transaminase elevations <5× normal without bilirubin elevation, continue treatment with close monitoring 3
• If hepatotoxicity develops in acutely ill patients with infectious TB (e.g., cavitary disease), switch to non-hepatotoxic alternatives while awaiting normalization rather than stopping all therapy 3

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Therapeutic Drug Monitoring (TDM)

Indications for TDM in ICU Patients

Measure serum drug concentrations in all ICU patients with renal or hepatic impairment, as altered pharmacokinetics are universal in critical illness 2

Additional indications include:

• Slow response to treatment 2
• Multiple interacting medications (common in ESRD and HIV patients) 1, 2
• Malabsorption syndromes 2

Optimal Sampling Strategy

• Collect blood at 2 hours post-dose as the primary time point to capture peak concentrations (Cmax) for isoniazid, rifampin, pyrazinamide, and ethambutol 2
• Consider additional 6-hour sampling in patients with borderline renal function (CrCl 30-50 mL/min) to optimize dosing 1, 2

ICU-Specific Pharmacokinetic Concerns

• A South African ICU study found that 60% of critically ill patients achieved sub-therapeutic rifampin concentrations when given standard weight-based dosing via nasogastric tube 6
• Patients with sub-therapeutic rifampin levels had higher APACHE II scores and lower estimated GFR 6
• This underscores the critical importance of TDM in ICU patients, as standard dosing frequently fails to achieve therapeutic levels 6

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Drug Interactions in the ICU

Rifampin: Potent CYP450 Inducer

Rifampin significantly reduces levels of:

• Oral contraceptives 7
• Corticosteroids 7
• Oral anticoagulants 7
• Cyclosporin 7

Use TDM as the decisive tool for managing complex multi-drug interactions in ICU patients on multiple medications 2

Fluoroquinolones: CYP450 Inhibitors

• In contrast to rifampin, fluoroquinolones inhibit certain cytochrome isoenzymes, leading to reduced metabolism of concomitant drugs 7
• This is particularly relevant when treating multidrug-resistant TB in ICU patients 7

Antacid Interactions

• Aluminum hydroxide-containing antacids reduce ethambutol absorption by approximately 20% 4
• Avoid concurrent administration; separate ethambutol from antacids by at least 4 hours 4

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Pyridoxine (Vitamin B6) Supplementation

Give pyridoxine 25-50 mg daily with isoniazid to all ICU patients, as they universally meet high-risk criteria for neuropathy (critical illness, malnutrition, potential renal failure, advanced age) 1

• Increase to 100 mg daily if peripheral neuropathy develops 1

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Critical Pitfalls to Avoid

Never Reduce Doses in Renal Impairment

Reducing doses lowers peak concentrations and compromises concentration-dependent bacterial killing 1, 2

• Instead, extend the dosing interval to three times weekly 1
• This maintains therapeutic peak levels while preventing accumulation 1

Never Assume "Normal" Creatinine Means Normal Renal Function

Serum creatinine is misleading in elderly patients, those with low muscle mass, or patients on continuous renal replacement therapy (CRRT) 2

• Muscle mass decline can mask severe renal impairment 2
• Always calculate actual creatinine clearance using 24-hour urine collection 2

Never Ignore Bilirubin Elevation

Any rise in bilirubin mandates immediate cessation of hepatotoxic drugs, regardless of transaminase levels 3

• Bilirubin elevation indicates severe hepatocellular injury with higher mortality risk 3

Never Stop Treatment Prematurely for Asymptomatic Transaminase Elevations

• Asymptomatic elevations <5× normal without bilirubin rise do not require treatment interruption 3
• Premature cessation risks treatment failure and drug resistance 3

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Monitoring Schedule During ICU Treatment

• Monthly renal function assessment 5
• Monthly questioning about visual symptoms (blurred vision, color discrimination changes) 5, 4
• Monthly questioning about auditory/vestibular symptoms if injectable agents are used 5
• Liver function tests at baseline and with any clinical concern 3
• Serum drug concentration monitoring for ethambutol, cycloserine, or injectable agents in renal impairment 5