Tigecycline: Mechanism, Activity, Resistance, and Pharmacokinetics

Tigecycline, a glycylcycline antibiotic derived from minocycline, has become an important option in addressing multidrug-resistant bacterial infections. Its structural modifications enhance its efficacy where other antibiotics fail, offering clinicians a valuable tool against resistance.

The threat of antimicrobial resistance highlights the need to understand tigecycline’s role and limitations. Examining its mechanism, activity spectrum, resistance patterns, and pharmacokinetic properties will reveal both its therapeutic potential and the challenges in its use.

Mechanism of Action

Tigecycline targets the bacterial ribosome, responsible for protein synthesis, by binding to the 30S subunit. This action obstructs the attachment of aminoacyl-tRNA to the A site, halting the addition of new amino acids to the peptide chain and interrupting protein synthesis, essential for bacterial growth.

The addition of a glycylamido moiety enhances tigecycline’s binding affinity to the ribosome, allowing it to overcome common resistance mechanisms affecting other tetracyclines. It can evade efflux pump-mediated resistance and bypass ribosomal protection proteins that typically dislodge tetracyclines.

Spectrum of Activity

Tigecycline’s broad spectrum of activity includes many Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). It also targets various Gram-negative bacteria, like Acinetobacter baumannii and certain strains of Escherichia coli, known for rapid resistance development.

In treating atypical pathogens, tigecycline is effective against organisms like Mycoplasma pneumoniae and Chlamydophila pneumoniae, responsible for atypical pneumonia. It also combats anaerobic bacteria, including Bacteroides fragilis, common in intra-abdominal infections. However, tigecycline faces limitations against Pseudomonas aeruginosa and Proteus species, which exhibit intrinsic resistance, necessitating accurate microbial diagnosis and susceptibility testing.

Resistance

Despite its introduction as a solution to resistant infections, resistance to tigecycline has emerged. Mutations in ribosomal protein genes can alter the ribosome’s structure, reducing tigecycline binding. Increased expression of efflux pumps can also diminish the drug’s intracellular concentration, impacting its efficacy.

Plasmid-mediated resistance, involving genetic elements capable of horizontal transfer among bacteria, is particularly concerning as it facilitates rapid dissemination of resistance traits. This can occur even without direct antibiotic pressure, complicating efforts to contain resistance spread.

Pharmacokinetics and Pharmacodynamics

Tigecycline’s pharmacokinetic profile is characterized by extensive tissue penetration, achieving high concentrations in the lungs, liver, and inflammatory exudates. However, it does not achieve high plasma concentrations, affecting its efficacy against bloodstream infections.

The drug is primarily metabolized through non-enzymatic pathways, with elimination via biliary excretion. This requires caution in patients with liver impairment to avoid accumulation and potential toxicity. Its long half-life supports a twice-daily dosing regimen, maintaining therapeutic levels while minimizing adverse effects.

Tigecycline’s pharmacodynamics involve time-dependent killing action, with efficacy linked to the duration that drug concentrations remain above the minimum inhibitory concentration (MIC) for the target pathogen. Careful dosing is necessary to ensure effectiveness, especially against resistant organisms with elevated MICs.