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ARDS: ATS Clinical Practice Guideline (2024)

Note on the "2025" guideline: The most recent ATS ARDS-specific guideline was published January 2024 in Am J Respir Crit Care Med (Qadir N et al., 209(1):24–36, PMID: 38032683). The ATS guideline published in November 2025 addressed Community-Acquired Pneumonia (CAP), not ARDS. The 2024 ARDS guideline is the current standard.

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Berlin Definition of ARDS (Diagnostic Criteria)

Severity Classification

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ATS 2024 Guideline: The 5 Core Recommendations

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1. Systemic Corticosteroids ✅

• Recommendation: Suggest using corticosteroids for patients with ARDS.
• Rationale: Meta-analyses of RCTs (including DEXA-ARDS, LaSRS, and others) show reductions in mortality, duration of mechanical ventilation, and ICU length of stay.
• Practical considerations:
  • Most evidence supports methylprednisolone or dexamethasone
  • Commonly used regimens: dexamethasone 20 mg/day × 5 days → 10 mg/day × 5 days; or methylprednisolone 1 mg/kg/day
  • Caution: Risk of hyperglycemia, secondary infections, ICU-acquired weakness; avoid in patients with active uncontrolled infections
  • Benefit appears greatest in early, moderate-to-severe ARDS (not late fibroproliferative phase)

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2. Venovenous ECMO (VV-ECMO) ✅ (selected patients)

• Recommendation: Suggest using VV-ECMO in selected patients with severe ARDS.
• Key trials: CESAR (2009) and EOLIA (2018) — EOLIA showed no statistically significant 60-day mortality benefit, but high crossover rate (28%) confounded results; Bayesian analysis supported benefit.
• Patient selection criteria:
  • Reversible etiology of respiratory failure
  • Severe hypoxemia: PaO₂/FiO₂ < 80 mmHg or hypercapnia (pH < 7.25 with PaCO₂ > 60 mmHg)
  • Failure of conventional therapies (lung-protective ventilation, high PEEP, prone positioning, NMBAs)
  • Early phase of ARDS (< 7 days of mechanical ventilation)
  • Few risk factors for futility
• Implementation: Should be delivered at high-volume ECMO centers with multidisciplinary teams; as part of a comprehensive care package including lung-protective ventilation and prone positioning.

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3. Neuromuscular Blocking Agents (NMBAs) ✅ (early severe ARDS)

• Recommendation: Suggest using neuromuscular blockers in patients with early severe ARDS.
• Key trials: ACURASYS (2010) showed benefit; ROSE trial (2019) showed no mortality benefit with routine NMBA — however, ROSE used lighter sedation in control arm.
• Rationale: NMBAs may reduce patient self-inflicted lung injury (P-SILI), reduce dyssynchrony, facilitate lung-protective ventilation, and reduce oxygen consumption.
• Timing: "Early" = within first 48 hours of severe ARDS onset.
• Caution: ICU-acquired weakness risk; should not be used routinely in moderate ARDS without specific indication.
• Notable divergence from ESICM 2023: ESICM recommends against routine NMBA use in moderate-to-severe ARDS not due to COVID-19; ATS conditionally supports use in early severe ARDS.

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4. Higher PEEP (without LRMs) ✅ in moderate-to-severe ARDS

• Recommendation: Suggest using higher PEEP as opposed to lower PEEP in patients with moderate to severe ARDS.
• Key evidence: Meta-analyses of ALVEOLI, LOV, and ExPress trials showed mortality benefit in moderate-to-severe ARDS subgroup.
• Implementation: Higher PEEP strategies (e.g., PEEP ≥ 10–15 cmH₂O depending on FiO₂) are preferred; PEEP/FiO₂ tables from ARDSnet can guide titration.
• Important caveat: Higher PEEP should be used without accompanying prolonged lung recruitment maneuvers (see below).

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5. Against Prolonged Lung Recruitment Maneuvers (LRMs) ❌

• Recommendation: Recommend against using prolonged lung recruitment maneuvers in patients with moderate to severe ARDS.
• Key evidence: ART trial (2017) — high-pressure prolonged recruitment maneuvers (sustained inflation at 45 cmH₂O for 1 minute) significantly increased mortality compared to PEEP titration alone.
• Important distinction: This strong recommendation is specifically against prolonged LRMs (sustained high-pressure maneuvers); brief LRMs may have insufficient evidence to make a firm recommendation.

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Foundational Ventilation Strategies (from 2017 Guideline, still current)

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Summary Table: ATS 2024 ARDS Recommendations

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Clinical Approach to ARDS Management

1. Identify and treat the underlying cause (sepsis, pneumonia, aspiration, etc.)
2. Respiratory support: HFNC → NIV → intubation based on severity
3. Lung-protective MV: TV 6 mL/kg IBW, plateau ≤ 30 cmH₂O, driving pressure < 15 cmH₂O
4. Higher PEEP (no prolonged LRMs) in moderate-to-severe
5. Prone positioning ≥ 12 h/day in severe ARDS
6. NMBAs in early severe ARDS (first 48 h)
7. Corticosteroids — suggest use across ARDS severity
8. Conservative fluid strategy after initial resuscitation
9. VV-ECMO — consider in selected severe refractory ARDS at expert centers

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Acute Respiratory Distress Syndrome (ARDS): Comprehensive Review

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1. CAUSES OF ARDS

Direct (Pulmonary) Causes

Indirect (Systemic/Extrapulmonary) Causes

Risk Factors That Increase ARDS Susceptibility

• Chronic alcohol abuse
• Hypoproteinemia
• Advanced age
• High APACHE/ISS scores
• Blood transfusions
• Cigarette smoking
• Blood group A
• Ambient air pollution
• Protective: Diabetes mellitus, pre-hospital antiplatelet therapy (appear to reduce risk)

Source: Fishman's Pulmonary Diseases and Disorders — Table 141-4

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2. BERLIN DIAGNOSTIC CRITERIA FOR ARDS (2012)

The 4 Required Criteria

Severity Classification

Note: The 2024 Global ARDS Definition (Matthay et al., AJRCCM 2024) expanded the Berlin criteria to include non-intubated patients (high-flow oxygen, NIV, CPAP) and allows lung ultrasound as an imaging modality. SpO₂/FiO₂ ≤ 315 can substitute for PaO₂/FiO₂ when ABG is unavailable.

Source: Fishman's Pulmonary Diseases and Disorders, Tables 141-1A/B; Tintinalli's Emergency Medicine, Table 29B-1

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3. DIAGNOSIS OF ARDS IN THE EMERGENCY DEPARTMENT

Clinical Presentation

• Acute dyspnea (onset < 1 week)
• Tachypnea, tachycardia
• Hypoxemia refractory to supplemental oxygen
• Diffuse bilateral crackles
• Cyanosis
• Fever, cough (if infectious cause)
• ARDS is a diagnosis of exclusion — cardiogenic pulmonary edema must be ruled out

Diagnostic Approach

• History of sepsis, pneumonia, aspiration, trauma, pancreatitis, transfusion

• CXR: Bilateral alveolar opacities obscuring pulmonary vascular markings; may appear as "bat-wing" or "white-out" pattern. No Kerley B lines or cardiomegaly (differentiates from cardiogenic edema).
• CT chest: More sensitive; shows bilateral ground-glass opacities + dependent consolidation; gravity-dependent distribution; detects pneumothorax, effusions, barotrauma

• Calculate PaO₂/FiO₂ ratio (P/F ratio)
• Confirms severity classification
• Usually shows hypoxemia ± hypocapnia (early) or hypercapnia (late/severe)

• Echocardiography: Exclude left ventricular dysfunction, valvular disease; estimate PCWP indirectly
• BNP/NT-proBNP: Elevated in cardiogenic edema; normal/mildly elevated in ARDS
• Clinical context: No clinical evidence of left atrial hypertension

Differential Diagnosis of ARDS in ED

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4. INVESTIGATIONS IN ARDS

Bedside / Initial

Laboratory

Advanced / Targeted

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5. VENTILATOR MANAGEMENT OF ARDS

Goals of Ventilation

1. Maintain adequate oxygenation (SpO₂ 88–95%; PaO₂ 55–80 mmHg)
2. Avoid ventilator-induced lung injury (VILI): volutrauma, barotrauma, atelectrauma, biotrauma

Core ARDSNet / Lung-Protective Ventilation Strategy (ARMA Trial)

ARMA Trial (ARDSNet, 2000): TV 6 mL/kg vs 12 mL/kg PBW → mortality reduced from 39.8% to 31.0% (p=0.007); more ventilator-free days (12 vs 10, p=0.007) — Fishman's Pulmonary Diseases, Table 141-10

Calculating Predicted Body Weight (PBW)

• Male: PBW (kg) = 50 + 2.3 × (height in inches − 60)
• Female: PBW (kg) = 45.5 + 2.3 × (height in inches − 60)

PEEP Strategy (ATS 2024)

• Higher PEEP preferred over lower PEEP in moderate-to-severe ARDS (conditional, low-moderate certainty)
• Use ARDSNet PEEP/FiO₂ tables for titration
• No prolonged lung recruitment maneuvers (LRMs) — strong recommendation AGAINST (ART trial: increased mortality with sustained 45 cmH₂O inflation)

Permissive Hypercapnia

• Tolerate elevated PaCO₂ to allow safe low TV ventilation
• Accept pH as low as 7.20–7.25 if necessary
• Contraindications to permissive hypercapnia:
  • Raised intracranial pressure
  • Acute cerebrovascular disease/stroke
  • Severe pulmonary hypertension / RV failure
  • Acute myocardial ischemia
  • Severe metabolic acidosis
  • Pregnancy

Ventilator Mode Considerations

VILI Mechanisms and Prevention

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6. PRONE POSITIONING IN ARDS

Mechanism of Benefit

• Redistributes ventilation-perfusion; reduces V/Q mismatch and shunt
• Homogenizes distribution of tidal volumes (dorsal lung reopens)
• Reduces lung stress and strain
• Facilitates drainage of secretions
• Reduces pleural pressure gradient

Intubated Prone Positioning (Standard)

• 28-day mortality: 16% vs 32.8% (p<0.001) — NNT ≈ 6
• 90-day mortality: 23.6% vs 41%

• Strong recommendation for prone positioning > 12–16 hours/day in severe ARDS (PaO₂/FiO₂ < 150 mmHg)
• Should be continued until reversal of severe hypoxemia or inability to tolerate

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7. AWAKE PRONE POSITIONING IN ARDS

Rationale

• Improves oxygenation by the same V/Q redistribution mechanism as intubated proning
• May prevent or delay intubation
• Can be combined with HFNC or NIV
• Avoids risks of mechanical ventilation and sedation

Evidence

• COVID-19 context: Multiple RCTs and meta-analyses confirm improved oxygenation indices
• PMID: 37796372 (Graziani et al., Meta-analysis, 2024): Awake proning in COVID-related respiratory failure reduced intubation rates
• PMID: 38712558 (Freire et al., SR/MA, 2024): In unventilated severe COVID-19, awake proning did not significantly alter major outcomes (mortality, ICU LOS), though oxygenation improved
• PMID: 35909384 (Othman et al., RCT, 2023): Awake proning significantly improved SpO₂ and respiratory rate in non-intubated COVID ARDS patients
• Rosen's Emergency Medicine: "Awake proning... increases oxygenation... has shown some promise" — used alongside HFNC/NIV in ED

Protocol for Awake Proning

1. Patient selection: Cooperative, spontaneously breathing, hypoxemic (SpO₂ < 94% on supplemental O₂); no contraindications
2. Position: Full prone or lateral/semi-prone (30–45° head elevation)
3. Duration: Target ≥ 3–4 hours per session; multiple sessions per day if tolerated (cumulative ≥ 8–12 hours/day)
4. Monitoring: Continuous SpO₂, respiratory rate, work of breathing
5. Response assessment: If SpO₂ fails to improve or work of breathing worsens → consider intubation

Contraindications to Awake Proning

• Altered mental status / uncooperative patient
• Immediate need for intubation
• Hemodynamic instability
• Facial/thoracic injury
• Recent abdominal surgery
• Pregnancy
• Morbid obesity (relative)

Response Criterion

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8. OVERALL MANAGEMENT OF ARDS

Step-by-Step Approach

ARDS Diagnosed
      ↓
1. Treat Underlying Cause (sepsis → antibiotics, aspiration → supportive, etc.)
      ↓
2. Respiratory Support Escalation:
   Mild ARDS → HFNC ± Awake Proning
   Moderate/Severe → Intubation + Mechanical Ventilation
      ↓
3. Lung-Protective MV: TV 6 mL/kg PBW, Pplat ≤30, Higher PEEP
      ↓
4. Prone Positioning ≥16 h/day if PaO₂/FiO₂ <150
      ↓
5. Neuromuscular Blockade (early severe ARDS, first 48 h)
      ↓
6. Corticosteroids (conditional — suggest use across severity)
      ↓
7. Conservative Fluid Strategy (post-resuscitation)
      ↓
8. VV-ECMO (refractory severe ARDS at ECMO-capable center)

Pharmacological Management

Corticosteroids — Practical Use

• Dexamethasone: 20 mg/day × 5 days → 10 mg/day × 5 days
• Methylprednisolone: 1–2 mg/kg/day, taper over 2–4 weeks
• Avoid if: active uncontrolled infection, late fibroproliferative phase (> 14 days)
• Monitor: hyperglycemia, ICU-acquired weakness, secondary infections

Supportive Care

Complications to Monitor

• Pneumothorax / barotrauma
• Ventilator-associated pneumonia (VAP)
• Multiorgan dysfunction (renal, hepatic, hematologic)
• Pulmonary fibrosis (late, fibroproliferative phase)
• ICU-acquired weakness
• PTSD / post-ICU syndrome

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• Qadir N et al. ATS Clinical Practice Guideline: Management of ARDS. AJRCCM 2024;209(1):24–36. PMID 38032683
• Matthay MA et al. A New Global Definition of ARDS. AJRCCM 2024;209(1):37–47
• PROSEVA Trial. Guérin C et al. NEJM 2013;368:2159–2168
• ARDSNet ARMA Trial. NEJM 2000;342:1301–1308
• Fishman's Pulmonary Diseases and Disorders, 2-Volume Set
• Rosen's Emergency Medicine, Concepts and Clinical Practice
• Tintinalli's Emergency Medicine: A Comprehensive Study GuideHere is the complete, structured overview covering all your requested topics:

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ARDS: Complete Clinical Review

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1. CAUSES OF ARDS

Direct (Pulmonary) Causes

Indirect (Systemic/Extrapulmonary) Causes

Risk Factors for Developing ARDS (Given an Underlying Cause)

• Chronic alcohol abuse
• Hypoproteinemia
• Advanced age
• High injury severity score (ISS) or APACHE score
• Multiple blood transfusions
• Cigarette smoking
• Blood group A
• Protective: Diabetes mellitus, pre-hospital antiplatelet therapy

Fishman's Pulmonary Diseases and Disorders, Table 141-4

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2. BERLIN DIAGNOSTIC CRITERIA FOR ARDS (2012)

4 Required Criteria (ALL must be met)

Severity Stratification

2024 Global Definition Update (Matthay et al., AJRCCM 2024): Expanded to include non-intubated patients on HFNC/NIV; lung ultrasound accepted for imaging criterion; SpO₂/FiO₂ ≤ 315 can replace PaO₂/FiO₂ when ABG unavailable.

Fishman's Pulmonary Diseases, Tables 141-1B; Tintinalli's Emergency Medicine, Table 29B-1

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3. DIAGNOSIS OF ARDS IN THE EMERGENCY DEPARTMENT

Clinical Features

• Acute-onset dyspnea and tachypnea
• Hypoxemia refractory to supplemental O₂ (hallmark)
• Diffuse bilateral crackles on auscultation
• Tachycardia, cyanosis
• Fever, cough (if infectious etiology)

Emergency Diagnostic Approach

• Bilateral alveolar opacities obscuring vascular markings
• "Bat-wing" or "white-out" pattern
• Differentiates from cardiogenic edema: No Kerley B lines, no cardiomegaly, no upper lobe diversion (though overlap can occur)

• Calculate PaO₂/FiO₂ ratio (requires known FiO₂)
• Confirms severity and diagnosis
• Early ARDS: hypoxemia + hypocapnia (hyperventilation); Late/severe: hypercapnia + metabolic acidosis

• BNP/NT-proBNP: Low or normal favors ARDS; markedly elevated favors cardiogenic edema
• Echocardiography (POCUS): Assess LV function, wall motion abnormalities, valvular disease
• Clinical: No orthopnea/PND, no peripheral edema pattern, not responsive to diuretics

ED Chest Imaging: ARDS Appearance

Differential Diagnosis in the ED

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4. INVESTIGATIONS IN ARDS

Bedside / Immediate

Laboratory

Targeted / Advanced

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5. VENTILATOR MANAGEMENT OF ARDS

Overall Goals

1. Maintain SpO₂ 88–95% (PaO₂ 55–80 mmHg) — avoid excessive hyperoxia
2. Prevent VILI (volutrauma, barotrauma, atelectrauma, biotrauma)
3. Allow permissive hypercapnia if needed for safe low-volume ventilation

Lung-Protective Ventilation (ARDSNet ARMA Protocol)

ARMA Trial Result: Low TV (6 mL/kg) vs Traditional (12 mL/kg) → mortality 31% vs 39.8% (p=0.007) — Fishman's Pulmonary Diseases, Table 141-10

Calculating Predicted Body Weight (PBW)

• Male: 50 + 2.3 × (height in inches − 60)
• Female: 45.5 + 2.3 × (height in inches − 60)

Use PBW, NOT actual body weight — critical in obese patients

PEEP/FiO₂ Table (ARDSNet Higher PEEP Table for Moderate-Severe ARDS)

Lung Recruitment Maneuvers (LRMs)

• Strong recommendation AGAINST prolonged LRMs (ATS 2024)
• ART Trial (2017): Sustained inflation at 45 cmH₂O → significantly increased 28-day mortality
• Brief, step-wise LRMs: insufficient evidence; may be used with caution in selected cases

Permissive Hypercapnia

• Allow PaCO₂ to rise to maintain safe low TV ventilation
• Accept pH ≥ 7.20–7.25

Mechanisms of VILI (and Prevention)

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6. PRONE POSITIONING (INTUBATED) IN ARDS

Mechanisms

• Homogenizes distribution of tidal volumes (recruits collapsed dorsal lung)
• Reduces V/Q mismatch and intrapulmonary shunt
• Reduces pleural pressure gradient
• Facilitates secretion drainage

PROSEVA Trial (2013)

• Population: Severe ARDS (PaO₂/FiO₂ < 150 mmHg), early (< 36 h), on lung-protective MV
• Intervention: Prone ≥ 16 h/day vs supine
• 28-day mortality: 16% vs 32.8% (p<0.001); 90-day mortality: 23.6% vs 41%

ATS 2017 / Current Recommendation

• Strong recommendation for prone positioning ≥ 12–16 hours/day in severe ARDS (PaO₂/FiO₂ < 150 mmHg)
• Initiate early (within 36 hours of MV)
• Continue until hypoxemia resolves

Complications of Prone Positioning

• Pressure ulcers (face, chest, knees)
• Endotracheal tube displacement/obstruction
• Central line/arterial line dislodgement
• Facial edema
• Temporary hemodynamic instability during turning

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7. AWAKE PRONE POSITIONING IN ARDS

Definition

Physiologic Rationale

• Same V/Q redistribution as intubated proning
• Prevents "sinus" pattern lung injury (dorsal collapse in supine position)
• Reduces work of breathing over time
• May reduce risk of patient self-inflicted lung injury (P-SILI)
• Potential to avoid/delay intubation

Evidence

Key limitation: Most evidence is from COVID-19 ARDS. Benefit in general non-COVID ARDS is less clear. Should not delay necessary intubation.

Practical Protocol

Contraindications to Awake Proning

• Altered consciousness / uncooperative
• Immediate intubation criteria (GCS < 13, hemodynamic instability, impending arrest)
• Facial/thoracic trauma
• Recent abdominal surgery
• Hemoptysis
• Pregnancy
• Severe claustrophobia or agitation
• Morbid obesity (relative)

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8. COMPLETE MANAGEMENT SUMMARY

ARDS Suspected → Confirm Berlin Criteria
         ↓
1. TREAT UNDERLYING CAUSE
   Sepsis → broad-spectrum antibiotics + source control
   Pneumonia → antivirals/antibiotics
   Aspiration → supportive; antibiotics if secondary infection
   Pancreatitis → supportive; fluids
         ↓
2. RESPIRATORY SUPPORT (escalate based on severity)
   Mild ARDS → HFNC (target SpO₂ 92–96%) ± Awake Proning
   Moderate/Severe → Intubation + Mechanical Ventilation
         ↓
3. LUNG-PROTECTIVE VENTILATION
   TV: 6 mL/kg PBW | Pplat ≤ 30 | Driving pressure < 15
   Higher PEEP (without prolonged LRMs)
   Permissive hypercapnia if needed
         ↓
4. PRONE POSITIONING ≥16 h/day (if PaO₂/FiO₂ < 150)
         ↓
5. NMBAs — if early severe ARDS (first 48h), dyssynchrony
         ↓
6. CORTICOSTEROIDS — suggest use (conditional)
         ↓
7. CONSERVATIVE FLUID MANAGEMENT (post-resuscitation)
         ↓
8. VV-ECMO — refractory severe ARDS, ECMO-capable centre

ATS 2024 Recommendations Summary

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Berlin Definition of ARDS (2012) — Complete

Background

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Conceptual (Pathophysiological) Definition

"ARDS is an acute, diffuse, inflammatory lung injury leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue — characterized by hypoxemia and bilateral radiographic opacities, associated with increased venous admixture (shunting), increased physiological dead space, and decreased lung compliance." — ARDS Definition Task Force, JAMA 2012

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The 4 Diagnostic Criteria (ALL must be present)

Criterion 1 — TIMING

Acute onset within 1 week of a known clinical insult, OR new or worsening respiratory symptoms

• "Acute" is operationally defined as ≤ 7 days from the triggering event
• Most cases occur within 72 hours of the precipitating cause
• This replaces the vague AECC term "acutely"

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Criterion 2 — CHEST IMAGING

Bilateral opacities on chest radiograph or CT — not fully explained by effusions, lobar/lung collapse, or nodules

• Opacities must be bilateral (involving both lung fields)
• They must be consistent with pulmonary edema in appearance
• They cannot be fully attributed to:
  • Pleural effusions
  • Lobar or whole-lung atelectasis/collapse
  • Nodules/masses
• CT chest is acceptable if CXR is technically inadequate
• Note: The 2024 Global Definition update also accepts lung ultrasound (bilateral B-lines / consolidation)

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Criterion 3 — ORIGIN OF EDEMA

Respiratory failure not fully explained by cardiac failure or fluid overload

• Excludes cardiogenic (hydrostatic) pulmonary edema as the primary cause
• No longer requires a pulmonary artery wedge pressure (PCWP) ≤ 18 mmHg (removed from Berlin definition)
• If no identifiable ARDS risk factor is present, objective assessment is required (e.g., echocardiography) to exclude hydrostatic/cardiogenic edema

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Criterion 4 — OXYGENATION

PaO₂/FiO₂ ratio ≤ 300 mmHg with PEEP or CPAP ≥ 5 cmH₂O

• Must be measured with the patient receiving at minimum PEEP or CPAP ≥ 5 cmH₂O
• This requirement was added because PEEP level significantly affects the P/F ratio — accounting for it removes variability in diagnosis
• The oxygenation criterion then determines severity

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Severity Stratification (Based on PaO₂/FiO₂ on PEEP ≥ 5 cmH₂O)

Important: The Berlin definition abolished the category of "Acute Lung Injury (ALI)." What was previously ALI (PaO₂/FiO₂ ≤300 but >200) is now Mild ARDS. ALI is an obsolete term.

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Complete Berlin Definition Table

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Key Improvements Over the 1994 AECC Definition

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Important Notes on Applying the Criteria

1. PEEP requirement: The P/F ratio must be obtained while the patient is on PEEP/CPAP ≥ 5 cmH₂O. A patient breathing room air or on minimal oxygen may not meet the oxygenation criterion even if hypoxemic — they need to be formally tested.
2. Not a diagnosis of exclusion per se, but cardiac failure must be ruled out. If no clear ARDS risk factor exists, echocardiography is required to confirm non-cardiogenic etiology.
3. Severity is dynamic — a patient can transition between severity categories as the disease progresses or responds to treatment. Severity at 24 hours after diagnosis carries stronger prognostic value than at initial presentation.
4. Histological correlation: The Berlin definition has imperfect concordance with diffuse alveolar damage (DAD) on autopsy — DAD is confirmed in ~45% of mild, ~72% of moderate, and ~58% of severe ARDS cases, indicating the clinical definition is broader than pure DAD.

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Latest TB Drug Regimens

• ATS/CDC/ERS/IDSA 2025 Updated Clinical Practice Guideline (Ann Am Thorac Soc, 2025 — PMC11755361)
• WHO Consolidated Guidelines Module 4: DR-TB Treatment (2022 update)
• Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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PART 1: LATENT TB INFECTION (LTBI) — Preventive Therapy

⚠️ Rifampin + Pyrazinamide (2RZ) for 2 months is NO longer recommended — unacceptable rates of hepatotoxicity and death. Caution with rifamycin-based LTBI regimens in HIV+ patients due to drug interactions with ART.

Harrison's 22e, 2025 | Lippincott Pharmacology

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PART 2: ACTIVE DRUG-SUSCEPTIBLE TB (DS-TB)

Standard 6-Month Regimen (Gold Standard)

• Cavitary disease on CXR AND positive sputum culture at 2 months
• 2-month course of pyrazinamide not completed
• HIV-infected, not receiving ART
• Delayed culture conversion (positive cultures beyond 2 months)

• TB meningitis (continuation phase 10 months total; add dexamethasone)
• Bone/joint TB — some guidelines recommend 9 months total

NEW: 4-Month Regimen for DS-TB ⭐ (2022–2025 Update)

• Noninferior to 6-month standard in large multinational RCT
• Conditional recommendation by WHO and ATS/CDC/ERS/IDSA 2025
• Applicable to HIV+ patients with CD4 > 100
• Requires fluoroquinolone resistance testing before use in high-resistance settings
• Higher daily pill burden than standard regimen

Standard Drug Doses (Adults)

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PART 3: DRUG-RESISTANT TB (DR-TB)

Classification

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A. 6-Month BPaLM Regimen ⭐⭐ (WHO 2022 / ATS 2025 — STRONG Recommendation)

• Based on TB-PRACTECAL trial: 89% favourable outcome vs ~52% with standard regimens
• All-oral regimen; no injectables
• Strong recommendation by ATS/CDC/ERS/IDSA 2025 over ≥15-month regimens
• WHO 2022 recommendation for MDR/RR-TB and pre-XDR-TB aged ≥14 years without prior BPaL exposure

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B. 6-Month BPaL Regimen ⭐⭐ (For Fluoroquinolone-Resistant / Pre-XDR-TB / XDR-TB)

• Based on ZeNix and Nix-TB trials: 90% favourable outcome in XDR-TB (vs ~50% historical controls)
• FDA approved 2019; Strong recommendation in ATS 2025 guidelines
• ⚠️ Linezolid toxicity significant: peripheral neuropathy, myelosuppression, optic neuropathy in >60% of patients — dose reduction to 600→300 mg acceptable

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C. 9-Month All-Oral Short Course ⭐ (WHO 2022)

• Replaced the old injectable-containing 9-month "Bangladesh" regimen
• All oral; shorter than previous 18–24 month regimens
• Conditional recommendation by WHO

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D. Longer Individualized MDR-TB Regimen

• Regimen should contain at least 4 effective drugs in the intensive phase and at least 3 in the continuation phase
• Treat for 15–21 months after culture conversion (5–7 months intensive phase)
• Injectable aminoglycosides (amikacin, kanamycin) now downgraded to Group C — used only when no oral alternatives available due to ototoxicity/nephrotoxicity

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E. Isoniazid Monoresistant TB

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PART 4: TB + HIV CO-INFECTION

• Start ART within 2 weeks of TB treatment initiation if CD4 < 50/μL
• Start ART within 8–12 weeks of TB treatment if CD4 ≥ 50/μL
• Exception: TB meningitis — delay ART to reduce immune reconstitution inflammatory syndrome (IRIS) risk
• Rifampin-ART interactions: Rifampin is a strong CYP3A4 inducer — reduces levels of protease inhibitors, NNRTIs, integrase inhibitors
  • Preferred ART with rifampin: efavirenz-based regimen or dolutegravir 50 mg twice daily
  • Consider rifabutin (weaker inducer) instead of rifampin when using boosted PI regimens

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PART 5: SPECIAL POPULATIONS

TB Meningitis

• Same 4-drug intensive phase (HRZE) for 2 months, then HR for 10 months (total 12 months)
• Add dexamethasone (0.4 mg/kg/day, tapering over 6–8 weeks) — reduces mortality
• Pyrazinamide penetrates CSF well; important component

Bone/Joint TB

• Standard 6-month HRZE/HR; some guidelines extend continuation phase to 7 months (total 9 months)

Pregnancy

• Standard HRZE/HR regimen; avoid streptomycin (ototoxicity to fetus)
• 3HP (isoniazid + rifapentine) NOT recommended in pregnancy
• Add pyridoxine (B₆) with isoniazid

Paediatric TB

• Same drug regimens as adults (weight-based dosing)
• Ethambutol: 20 mg/kg/day
• 3HP for LTBI approved for children >2 years

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Summary: Regimen Quick Reference

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• Daley CL et al. ATS/CDC/ERS/IDSA 2025 Updated TB Treatment Guideline. PMC11755361
• WHO Consolidated Guidelines Module 4: DR-TB Treatment, 2022 Update
• Harrison's Principles of Internal Medicine, 22nd ed., 2025
• Murray & Nadel's Textbook of Respiratory Medicine
• Nix-TB Trial (BPaL, NEJM 2020) | ZeNix Trial (NEJM 2022) | TB-PRACTECAL Trial (Lancet 2022) | Study 31/A5349 (NEJM 2021)