Beta-Lactamases

Mechanism of Action

• Serine beta-lactamases (Classes A, C, D): Use an active-site serine residue in a two-step reaction - acylation (covalent attachment of the antibiotic to the serine) followed by deacylation (hydrolysis releases the inactivated antibiotic and regenerates the enzyme).
• Metallo-beta-lactamases (Class B): Use one or two zinc ions at the active site to coordinate a water molecule that directly hydrolyzes the ring - no covalent intermediate, which is why these are NOT inhibited by classical beta-lactamase inhibitors.

Classification (Ambler Molecular Classes)

Clinically Important Types

• Derived from TEM and SHV penicillinases by point mutations, or the CTX-M family (now most common globally)
• Hydrolyze penicillins, all cephalosporins, and aztreonam
• Inhibited by clavulanic acid, sulbactam, and tazobactam
• Produced mainly by Enterobacteriaceae (especially E. coli, K. pneumoniae)
• Treatment: carbapenems remain the gold standard

• Class C, typically chromosomally encoded and inducible
• Produced by "SPACE" organisms: Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter
• NOT inhibited by clavulanic acid, tazobactam, or sulbactam
• Resistant to cephamycins (cefoxitin)

• Hydrolyze carbapenems - the last-resort beta-lactams
• KPC (Klebsiella Pneumoniae Carbapenemase): Class A, inhibited by avibactam; found in K. pneumoniae and other Enterobacteriaceae
• NDM (New Delhi Metallo-beta-lactamase): Class B MBL, resistant to virtually all beta-lactams; NOT inhibited by avibactam
• OXA-48: Class D, carbapenem-resistant K. pneumoniae; partially inhibited by avibactam

Beta-Lactamase Inhibitors

Genetic Transmission

• Chromosomal (intrinsic, often inducible - e.g., AmpC in Enterobacter)
• Plasmid-encoded (transferable by conjugation between organisms - e.g., TEM/SHV/CTX-M ESBLs, KPC, NDM)

• Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 1318-1337
• Henry's Clinical Diagnosis and Management by Laboratory Methods, Table 58.1 (Beta-Lactamase Classification)

Penicillin G vs. Amoxicillin: Same MOA?

Shared Mechanism of Action

"Penicillins interfere with the last step of bacterial cell wall synthesis, which is the cross-linking of adjacent peptidoglycan strands by a process known as transpeptidation. Since penicillins structurally resemble the terminal portion of the peptidoglycan strand (D-Ala-D-Ala), they compete for and bind to enzymes called penicillin-binding proteins (PBPs), which catalyze transpeptidase and facilitate cross-linking."

1. The beta-lactam ring mimics the D-Ala-D-Ala terminus of the peptidoglycan precursor
2. PBPs (which are transpeptidases, carboxypeptidases) bind the drug covalently
3. Cross-linking of peptidoglycan strands is blocked
4. The cell wall becomes structurally weak
5. Osmotic lysis and bacterial cell death follow (bactericidal effect)

Figure: Peptidoglycan cross-linking blocked by penicillins (Lippincott Pharmacology)

Where They Differ

Why Amoxicillin Has a Broader Spectrum

• Makes it more hydrophilic
• Allows better penetration through gram-negative outer membrane porin channels
• Extends activity to organisms like H. influenzae, E. coli, Enterococcus faecalis, Listeria

Summary

• Lippincott Illustrated Reviews: Pharmacology, p. 942-943
• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 1170, 753
• Katzung's Basic and Clinical Pharmacology, 16th Ed.

NTEP (RNTCP) Guidelines: Treatment of Drug-Resistant TB (November 2024)

Note: RNTCP was renamed the National TB Elimination Programme (NTEP) in 2020. The most current guidelines are the National Guidelines for Management of Drug Resistant TB, November 2024, published by the Central TB Division, MoHFW, Government of India. India aims to eliminate TB by 2025, 5 years ahead of the global SDG target.

Key 2024 Updates

1. Introduced BPaLM (6-month all-oral regimen) under programmatic conditions countrywide (approved September 2024)
2. Bdq and Dlm extended to all age groups (including children), given unmet need
3. Linezolid replaces ethionamide in the 9-11 month shorter oral MDR/RR-TB regimen

Classification of Drug-Resistant TB

Treatment Regimens

Regimen 1: BPaLM - 6-Month All-Oral Regimen (PREFERRED for eligible MDR/RR-TB)

• MDR/RR-TB (pulmonary, confirmed)
• No prior exposure to Bdq, Pa, or Lzd for >1 month
• No resistance to Bdq, Pa, or Dlm detected
• Age ≥14 years (pretomanid safety data not established below this)
• Not pregnant (pretomanid contraindicated in pregnancy)

Regimen 2: BPaL - 6-Month Regimen (for Pre-XDR-TB / FQ-resistant MDR-TB)

• Used when moxifloxacin cannot be given (FQ resistance or intolerance)
• Based on NIX-TB trial: 90% treatment success in Pre-XDR-TB
• Linezolid 1200 mg (original NIX-TB dose) replaced with 600 mg in NTEP due to lower toxicity while maintaining efficacy (ZeNix trial)

Regimen 3: 9-11 Month Shorter Oral Bedaquiline-Containing Regimen

• Linezolid (Lzd) replaces ethionamide (Eto) - 2024 key update
• 2 months of Lzd (600 mg) used as alternative to 4 months of Eto

• MDR/RR-TB without prior SLD exposure for >1 month
• No FQ resistance
• No extensive pulmonary disease
• No severe extra-pulmonary TB

Regimen 4: Longer All-Oral Regimen (≥18 months)

Special Population: Children (<14 years)

• BPaLM: Pretomanid not yet cleared for <14 years
• Bedaquiline and Delamanid approved for all age groups (2024 update)
• Alternative: BDLLfxC (Bdq + Dlm + Lzd + Levofloxacin + Clofazimine) - 6-month regimen for children ineligible for BPaLM

Pregnancy

• Pretomanid is contraindicated
• Longer individualized oral regimen used
• Avoid injectables

HIV co-infection

• Manage drug-drug interactions: Bdq and antiretrovirals (esp. efavirenz, lopinavir - QTc prolongation risk)
• BPaLM can be used with close monitoring

Diagnosis for DR-TB (2024 Updates)

• CBNAAT (GeneXpert MTB/RIF): First-line rapid test - detects RR-TB
• CBNAAT MTB/XDR test: Approved 2024 - detects resistance to H, FQ, SLI (second-line injectables), and Eto simultaneously
• Line Probe Assay (LPA): For detecting H and FQ resistance
• Liquid culture + DST: Confirmatory and for full resistance profiling
• Baseline LC-DST for Bdq, Lzd, Pa, Dlm, Z, Mfx recommended at follow-up

Monitoring During Treatment

Treatment Outcomes (NTEP Definitions)

Summary of Regimen Selection

MDR/RR-TB confirmed
        |
        ├─ Eligible for BPaLM? (age ≥14, not pregnant, no FQ resistance, no prior Bdq/Pa/Lzd)
        │         ↓ YES
        │    BPaLM × 26 weeks (PREFERRED)
        │
        ├─ FQ resistant (Pre-XDR-TB)?
        │         ↓ YES
        │    BPaL × 26 weeks
        │
        ├─ Not eligible for above, eligible for shorter oral regimen?
        │         ↓ YES
        │    9-11 month Bdq-containing regimen (Lzd replaces Eto)
        │
        └─ XDR-TB / treatment failure / ineligible above?
                  ↓
         Longer individualized oral regimen ≥18 months
         (WHO Group A+B+C priority)

• NTEP National Guidelines for Management of DR-TB, November 2024 (official PDF, Central TB Division, MoHFW India)
• Harrison's Principles of Internal Medicine 22E (2025), Table 183-4 / 186-4 - WHO drug classification and MDR-TB regimens
• Murray & Nadel's Textbook of Respiratory Medicine - BPaL regimen evidence (Nix-TB trial)