Cyclic Lipopeptides and Polymyxins

Membrane Destroyer Agents

Daptomycin and colistin are agents with physical bactericidal action that destroy the cell membrane of multidrug-resistant bacteria. Its therapeutic range requires caution in its usual clinical dosage.

Mechanism

💊 Generic and Commercial Names

Lipopéptidos: Daptomicina (Cubicin). Polimixinas: Colistina / Colistimetato de Sódio (Coly-Mycin, Promixin).

🔬 Pharmacological Group

Lipopéptidos cíclicos (Gram-positivos) y polimixinas o tensioactivos lipídicos (Gram-negativos). Destructores de membrana dural.

Mechanism of Action

Su blanco destruye de forma física el gradiente electroquímico de la membrana celular:

Despolarización de Membrana de Daptomicina (Gram-Positivos): Se une de forma específica a la membrana citoplasmática bacteriana mediante una interacción electrostática dependiente de cationes de calcium (Ca²⁺). Al captar calcio, su cola lipídica se inserta en la membrana lipídica de bacterias Gram-positivas, induciendo la agregación del fármaco en oligómeros durales que forman canales de flujo iónico por los que se produce una salida masiva y descontrolada de potasio (K⁺). Esto provoca la despolarización y muerte bacteriana rápida sin lisis celular.
Efecto Detergente de Colistina (Polimixina E - Gram-Negativos): Actúa como un tensioactivo catiónico. Se une electrostáticamente a los fosfatos de carga negativa del Lípido A del lipopolisacárido (LPS) de la membrana externa de Gram-negativas, desplazando a los cationes de calcio y magnesio estabilizadores. La porción lipídica hidrófoba de colistina penetra entonces la membrana externa e interna, provocando una disrupción estructural de tipo detergente con pérdida de la integridad celular y posterior lisis osmótica bacteriana.

Pharmacokinetics

Key Pharmacokinetics

Parameter	Daptomycin	Colistimethate Sodium (CMS - Prodrug) / Colistin
Routes of Administration	Exclusively rapid IV or 30 minute infusion.	IV (in the form of CMS), Inhaled (for Pseudomonas in cystic fibrosis).
Distribution and Tissues	Very low (0.10 L/kg). Predominantly confined to the circulatory space; excellent penetration into fatty tissues; negligible CSF penetration.	Low (0.25 - 0.35 L/kg). Poor penetration into CSF, intra-articular and pleural space.
Protein Binding	Extremely high (~90-93% bound to albumin).	Low (~50% bound to proteins).
Metabolism	Does not undergo classic hepatic metabolism; It is cleared through the urine in an unchanged form (50%).	CMS is slowly hydrolyzed non-enzymatically in plasma to active colistin with mixed excretion.
Excretion and Half-Life	Renal glomerular excretion unchanged at 50-60%. Elimination half-life of 8.0 to 9.0 hours.	Majority renal glomerular excretion for CMS; Active colistin is cleared non-renally. Half-life of 14.0 hours for the active fraction.

Antimicrobial Spectrum

Daptomycin: Excellent against multidrug-resistant Gram-positive cocci, including MRSA, VRE (Enterococcus faecalis and Enterococcus faecium resistant to vancomycin), resistant pneumococcus and severe nosocomial staphylococci.
Colistin: Last-line ultra-limited nosocomial Gram-negative spectrum. Active against carbapenemase- and MBL-producing Enterobacteriaceae, with excellent coverage against Pseudomonas aeruginosa and Acinetobacter baumannii with a multidrug-resistant course. Does not innately cover Proteus spp., Serratia spp. or Providencia spp.

Indicators and dose

Dosage and Adjustment

Daptomycin: 6 to 8 mg/kg every 24 hours by IV route (in severe VRE bacteremia or MRSA endocarditis, the recommended dose is increased to 10 to 12 mg/kg every 24 hours).
Colistimethate Sodium (CMS): Loading dose of 9 MIU IV, followed by a usual maintenance dose of 4.5 MIU every 12 hours IV (equivalent to 150 mg CBA every 12 hours).
Adjustment of Daptomycin in Renal Failure:
- Cl_cr < 30 mL/min: Extend the daptomycin dosing interval to every 48 hours (for both 6 and 8 mg/kg doses), with serum CK monitoring every 48 hours.

Security

Contraindications and ADRs

Contraindications: Demonstrated hypersensitivity to colistin or daptomycin.
Adverse Effects (ADR):
- Inactivation by Pulmonary Surfactant of Daptomycin: Daptomycin binds irreversibly and with high affinity to the pulmonary surfactant of the alveolus, immediately inactivating its analgesic lipid tail. For this reason, it is absolutely contraindicated for the management of pneumonia of any type, since it does not reach effective levels in the lung parenchyma.
- Daptomycin Myopathy and Rhabdomyolysis: Elevation of plasma creatine kinase (CK), diffuse proximal muscle pain and risk of severe rhabdomyolysis, with a reversible course after withdrawing the drug. Requires weekly CK monitoring.
- Nephrotoxicity of Colistin (Very common - 30-50%): Acute renal tubular necrosis due to increased permeability of tubular cells. It is associated with high accumulated doses.
- Neurotoxicity of Colistin: Perioral and distal paresthesias, neuromuscular weakness, mental confusion, seizures. Reversible after discontinuation of the dose.

Colistimethate Sodium (CMS) Dosing Alert

The prescription of Colistin is associated with a high risk of serious errors due to the confusing use of different nomenclatures worldwide: Millions of International Units (MUI) versus Milligrams of Colistin Base Activity (CBA). One milligram of CBA is equivalent to 2.4 MIU of CMS (approximately 30,000 IU of colistimethate). The nomenclature recommended by the local manufacturer must be strictly specified to prevent lethal overdoses due to acute renal failure or ineffective subtherapeutic doses.

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

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System: Antimicrobial and Infectious
Cluster: Membrane Destroyer Agents

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