Supramolecular gels of poly-α-cyclodextrin and PEO-based copolymers for controlled drug release

The aim of this work was to prepare syringeable supramolecular gels of α-cyclodextrin-polymer (poly-αCD) with various poly(ethylene oxide) (PEO)-based copolymers, which can be suitable to form depots for controlled drug release. A series of water-soluble poly-αCDs was synthesized from αCD by crosslinking with epichlorohydrin in alkaline medium. The chemical composition of the polymers was characterized by NMR (αCD content > 53%) and the molecular weight was evaluated using static light scattering (SLS). Supramolecular assemblies occurred by mixing poly-αCD (20–40% w/v) with a PEO-based polymer (i.e., PEG, Pluronic® F127 or Tetronic® 908) (10–15% w/v). Phase separation was observed and the αCD content in each phase was determined by means of the phenol–sulfuric acid colorimetric method. Formation of poly-αCD/PEO-based polymer 3D-supramolecular complexes was confirmed by diffusion-ordered NMR spectroscopy (DOSY) and X-ray diffractometry. The supramolecular assemblies showed good cytocompatibility against SAOS-2 cells and in the HET-CAM test. The supramolecular gels were able to sustain the release of vancomycin for at least 5 days at 37 °C, more efficiently than dispersions of each polymer component in separate. These results open new possibilities in the design of novel controlled delivery systems for the treatment of bone infections.     

Multivesicular liposome formulations for the sustained delivery of interferon α-2b

AIM: To develop and optimize a sustained release multivesicular liposome (MVL) formulation of interferon (IFN) alpha-2b. METHODS: IFN alpha-2b MVL were prepared using a typical double-emulsion procedure. The sustained release effects of IFN alpha-2b MVL were investigated by monitoring the blood IFN alpha-2b concentration using an enzyme-linked immunosorbent assay test after subcutaneous administration to healthy mice. RESULTS: IFN alpha-2b was successfully encapsulated in MVL with high efficiency, and the integrity of encapsulated protein was maintained. After subcutaneous injection, the MVL slowly released IFN alpha-2b into systemic circulation in a sustained manner. The estimated serum half-life of IFN alpha-2b was approximately 30 h. In addition, varying the size of the MVL preparations could further modify the in vivo release profile. CONCLUSION: IFN alpha-2b MVL may be a useful sustained release formulation in the clinical treatment of viral diseases.     

Proprietary Rel-Ease™ drug delivery technology: opportunity for sustained delivery of peptides,proteins and small molecules

Proprietary Rel-Ease? (Praecis Pharmaceuticals) drug delivery technology uses biocompatible polymers as carriers to incorporate a drug into a polymer matrix through opposite charge interaction or complexation. The resulting low solubility complexes can be used to prepare sustained release depot injections or potentially sustained release formulations for oral administration. As a regulatory approved and commercialised drug delivery technology, Rel-Ease is used in abarelix for injectable suspension, a monthly depot injection for the treatment of patients with advanced prostate cancer. The technology offers high drug loading and minimal-to-no initial burst effect in vivo. It uses aqueous processes and is compatible for complexation with many peptide and protein therapeutics; its mechanism can also be applied to many small-molecule therapeutics and offers conventional and alternative methods for sustained release delivery via an oral route.     

Curcumin-loaded γ-cyclodextrin liposomal nanoparticles as delivery vehicles for osteosarcoma

The delivery of curcumin, a broad-spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma (OS). Curcumin is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin's potential was evaluated against cancer models of mesenchymal (OS) and epithelial origin (breast cancer). The resulting 2-Hydroxypropyl-γ-cyclodextrin/curcumin - liposome complex shows promising anticancer potential both in vitro and in vivo against KHOS OS cell line and MCF-7 breast cancer cell line. An interesting aspect is that liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro in comparison with DMSO-curcumin induced autophagic cell death. In addition, the efficiency of the liposomal curcumin formulation was confirmed in vivo using a xenograft OS model. Curcumin-loaded γ-cyclodextrin liposomes indicate significant potential as delivery vehicles for the treatment of cancers of different tissue origin. FROM THE CLINICAL EDITOR: Curcumin-loaded γ-cyclodextrin liposomes were demonstrated in vitro to have significant potential as delivery vehicles for the treatment of cancers of mesenchymal and epithelial origin. Differences between mechanisms of cell death were also evaluated.     

A novel lactoferrin-modified β-cyclodextrin nanocarrier for brain-targeting drug delivery

The blood–brain barrier (BBB) restricts the transfer and delivery of most drug substances to brain. In this study, a novel nano-drug delivery system for brain-targeting was developed and investigated in vitro and in vivo. Lactoferrin (Lf) was selected as a brain-targeting ligand and conjugated to β-cyclodextrin (β-CD) via the heterobifunctional polyethyleneglycol (PEG) linker NHS-PEG-MAL, yielding Lf conjugated β-cyclodextrin (Lf-CD). UV–vis, FTIR, NMR and transmission electron microscopy (TEM) techniques clearly demonstrated the successful synthesis of Lf-CD nanoparticles with the average diameter of 92.9 ± 16.5 nm. Using near-infrared fluorescent dye IR-775 chloride (IR) as a model compound of poorly water-soluble drugs, IR-loaded Lf-CD nanoparticles (Lf-CD/IR) were successfully prepared with a high entrapment efficiency of 98.1 ± 4.8%. Biodistribution and pharmacokinetics of Lf-CD/IR were evaluated in KM mice after intravenous administration. The results of tissue distribution studies revealed that Lf-CD/IR treatment showed greatly improved BBB transport efficiency. In addition, AUC_0–2 h of IR in brain after Lf-CD/IR treatment was seven fold higher compared with that of IR treatment without Lf-CD nano-carriers, demonstrating that the introduction of Lf-CD drug-delivery system positively resulted in a higher AUC located in brain tissue. These results provide evidence that Lf-CD nanoparticles could be exploited as a potential brain-targeting drug delivery system for hydrophobic drugs and diagnostic reagents which normally fail to pass through the BBB.     

Hybrid lipid–polymer nanoparticles for sustained siRNA delivery and gene silencing

The development of controlled-release nanoparticle (NP) technologies has great potential to further improve the therapeutic efficacy of RNA interference (RNAi), by prolonging the release of small interfering RNA (siRNA) for sustained, long-term gene silencing. Herein, we present an NP platform with sustained siRNA-release properties, which can be self-assembled using biodegradable and biocompatible polymers and lipids. The hybrid lipid–polymer NPs showed excellent silencing efficacy, and the temporal release of siRNA from the NPs continued for over one month. When tested on luciferase-expressed HeLa cells and A549 lung carcinoma cells after short-term transfection, the siRNA NPs showed greater sustained silencing activity than lipofectamine 2000-siRNA complexes. More importantly, the NP-mediated sustained silencing of prohibitin 1 (PHB1) generates more effective tumor cell growth inhibition in vitro and in vivo than the lipofectamine complexes. We expect that this sustained-release siRNA NP platform could be of interest in both fundamental biological studies and clinical applications.From the Clinical EditorEmerging gene silencing applications could be greatly enhanced by prolonging the release of siRNA for sustained gene silencing. This team of scientists presents a hybrid lipid-polymer nanoparticle platform that successfully accomplishes this goal, paving the way to future research studies and potential clinical applications.     

Iluvien™: a new sustained delivery technology for posterior eye disease

Iluvien^? (fluocinolone acetonide intravitreal insert, Alimera Sciences, Inc.), a novel injectable intravitreal insert, is being studied to deliver a very low dose of a corticosteroid to the retina for up to 3 years as a treatment for diabetic macular edema. Using a proprietary 25-gauge injector system, an ophthalmologist injects the Iluvien insert, which uses the Medidur^? (Alimera Sciences, Inc.) technology, into the vitreous through a minimally invasive procedure in an out-patient setting. The placement of the device in the inferior vitreous has the potential to maximize drug at the retina while reducing exposure of the anterior chamber. Phase III studies are underway to test the safety and efficacy of Iluvien. This article offers a specific review of the Iluvien technology rather than an overview of the various intravitreal methods of treating posterior eye disease.     

Development of solid nanoparticles based on hydroxypropyl-β-cyclodextrin aimed for the colonic transmucosal delivery of diclofenac sodium

Objectives Nanoparticles were designed for the oral administration and transmucosal colon delivery of drugs. Methods Preparation parameters were studied in order to develop solid pH‐dependent drug‐release nanoparticles, constituted by hydroxypropyl‐β‐cyclodextrin and/or Eudragit^® L100 loaded with diclofenac sodium. Nanoemulsions were prepared by the emulsion‐evaporation method using various homogenizers. Different preparative conditions were tested. The emulsions obtained were analysed in terms of size and then dried to obtain solid nanoparticles which were characterized in vitro (particle size, morphology, dissolution, solid state characterization). The effect of nanoparticles on drug permeation through synthetic membranes, colonic pig mucosa and Caco2 cell line were performed. Toxicity studies were carried out to assess the safety of the raw materials used and the nanosystems produced. Key findings Appropriate parameters to obtain nanoemulsions stable enough to be desiccated were determined: Panda NS100L was the most suitable homogenizer for the preparation; particle size ranged between 100 and 600 nm depending on the production method. Solid nanoparticles were obtained by an exsiccation process, which does not modify the mean size. pH‐dependent drug‐release nanoparticles were obtained. The nanoencapsulation process decreased the crystallinity of the drug. Materials and nanoparticles were highly biocompatible. Transmucosal delivery of drug is dependent on the polymer and the test employed: cyclodextrin improved drug permeation across colonic pig mucosa. Conclusions Formulations containing hydroxypropyl‐β‐cyclodextrin represent new colon‐targeted nanoparticles for transmucosal delivery of drugs.     

Transdermal delivery of the in situ hydrogels of curcumin and its inclusion complexes of hydroxypropyl-β-cyclodextrin for melanoma treatment

Curcumin (Cur) is a hydrophobic polyphenol with diverse pharmacological effects, especially for cancer treatment. However, its weak water solubility and stability was the major obstacle for the formulation research of Cur. The complexation of Cur and hydroxypropyl-β-cyclodextrin (HP-β-CD) was done by grinding. The increasing solubility of Cur was achieved due to complexation and the photochemical stability of Cur was improved. The inclusion of Cur could happen when two ends of Cur were embedded into the cavity of the HP-β-CD rings. The in situ hydrogels (ISGs) of Cur and its inclusion complexes were prepared using poloxamers 407 and 188 as the matrix. The extent of drug’s in vitro release from the ISGs depended on the dissolution of drugs. Both of the ISGs had transdermal effect and cytotoxicity on B16-F10 cells. However, the effects of the ISGs containing Cur inclusion complexes were much higher than those of Cur ISGs because of the improved Cur solubility in the former. The cytotoxicity of Cur on melanoma cells was related to blocking of cellular proliferation in the G₂/M stage followed by cellular apoptosis. The ISGs of Cur inclusion complexes are a promising formulation for melanoma treatment.     

In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery

Introduction: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol–gel conversion on receipt of biological stimulus.

Areas covered: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed.

Expert opinion: The advent of in situ gel systems has inaugurated a new transom for ‘smart’ ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery

Parenteral sustained release drug formulations, acting as preferable platforms for longterm exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimal...     

Docosahexaenoic acid–mediated,targeted and sustained brain delivery of curcumin microemulsion

We disclose microemulsions (ME) of curcumin (CUR) with docosahexaenoic acid (DHA)-rich oil (CUR DHA ME) for targeted delivery to the brain. MEs of CUR (5?mg/mL) with and without DHA-rich oil (CUR Capmul ME) suitable for intravenous and intranasal administration exhibited negative zeta potential, globule size <20?nm and good stability. Following intravenous delivery MEs exhibited high brain concentration with CUR DHA ME exhibiting a 2.8-fold higher C_max than CUR solution. Furthermore, high and sustained concentration was demonstrated even at 24?h, which was 8- and 2-fold higher than CUR solution and CUR Capmul ME, respectively. Brain concentrations following intranasal administration were, however, substantially higher as evident from higher C_max and AUC and sustained compared to corresponding intravenous formulations signifying nose to brain targeting. The high brain concentration of CUR DHA ME is ascribed to the targeting efficiency enabled by DHA-mediated transport across the blood–brain barrier (BBB). Histopathological and nasal toxicity confirmed safety of the MEs. Concentration-dependent cytotoxicity in vitro, on human glioblastoma U-87MG cell line was observed with CUR DHA MEs and with the blank DHA ME, implying anticancer potential of DHA. The dramatically low IC₅₀ value of CUR DHA ME (3.755?±?0.24?ng/mL) is therefore attributed to the synergistic effect of CUR and DHA in the ME. The CUR concentration achieved with CUR DHA ME at 24 h which translated to >66-fold(intranasal) and >21–fold (intravenous) the IC₅₀ value in the U-87MG cell line suggests great promise of CUR DHA ME for therapy of brain cancer by both routes.     

Do cyclodextrins bound to dextran microspheres act as sustained delivery systems of drugs?

The use of cyclodextrins (CDs) for controlled delivery of drugs is largely presented in the literature. However, the question of whether CDs themselves linked to a polymeric network are able to sustain the release of drugs still persists. Here, CD immobilization within dextran microspheres is reported, and CD-dextran complexes were packed in a glass column and then, the retention time of different drugs and drug model compounds was determined by liquid chromatography. The release profiles of drugs and of drug model compounds (indole, 3-nitrophenol, p-hydroxybenzoic acid, diclofenac), characterized by different values of the retention time (high, moderate or low), were investigated. The release rates were quite high even for drugs that exhibit very high retention time (high association equilibrium constant). Moreover, the volume of the release fluid strongly influences the rate of drug release. As a whole, “the sink conditions” must be continuously maintained, since at each drug concentration in the release medium, equilibrium occurs between the free and the CD-bound drug.     

Doxycycline and hydroxypropyl-β-cyclodextrin complex in poloxamer thermal sensitive hydrogel for ophthalmic delivery

The present study aimed to prepare a chemically and physically stable formulation of doxycycline (Doxy) in an in situ thermally sensitive hydrogel for ophthalmic delivery. An inclusion complex of Doxy and hydroxypropyl-β-cyclodextrin (HP-β-CD) was first developed to increase the stability of Doxy in aqueous solution. The physical characteristics (phase solubility profiles, thermal analysis, X-ray powder diffractograms and infrared spectra) of the Doxy-HP-β-CD inclusion complex indicated the formation of a stable 1:1 complex. Poloxamers P407 (16–22%) and P188 (0–5%) were mixed to obtain a hydrogel with an appropriate gelation temperature for opthalmic use. Formulation of the inclusion complex in the poloxamer hydrogel exhibited a suitable gelation temperature (33.3 °C) after dilution with simulated tear fluid (Gel:STF=40:7, v/v). The release of Doxy from the poloxamer hydrogel followed a zero order equation suggesting it occurs through corrosion of the poloxamer hydrogel. Stability studies demonstrated that the inclusion of Doxy by HP-β-CD markedly improved its stability in aqueous solution both at 8 and 40 °C. This formulation of a doxycycline-HP-β-CD inclusion complex in an in situ thermally sensitive poloxamer hydrogel represents a potentially effective ophthalmic Doxy delivery system.     

Enhanced delivery efficiency and sustained release of biopharmaceuticals by complexation-based gel encapsulated coated microneedles: rhIFNα-1b example

Coated microneedles (MNs) are widely used for delivering biopharmaceuticals. In this study, a novel gel encapsulated coated MNs (GEC-MNs) was developed. The water-soluble drug coating was encapsulated with sodium alginate (SA) in situ complexation gel. The manufacturing process of GEC-MNs was optimized for mass production. Compared to the water-soluble coated MNs (72.02% ± 11.49%), the drug delivery efficiency of the optimized GEC-MNs (88.42% ± 6.72%) was steadily increased, and this improvement was investigated through in vitro drug release. The sustained-release of BSA was observed in vitro permeation through the skin. The rhIFNα-1b GEC-MNs was confirmed to achieve biosafety and 6-month storage stability. Pharmacokinetics of rhIFNα-1b in GEC-MNs showed a linearly dose-dependent relationship. The AUC of rhIFNα-1b in GEC-MNs (4.51 ng/ml·h) was bioequivalent to the intradermal (ID) injection (5.36 ng/ml·h) and significantly higher than water-soluble coated MNs (3.12 ng/ml·h). The rhIFNα-1b elimination half-life of GEC-MNs, soluble coated MNs, and ID injection was 18.16, 1.44, and 2.53 h, respectively. The complexation-based GEC-MNs have proved to be more efficient, stable, and achieve the sustained-release of water-soluble drug in coating MNs, constituting a high value to biopharmaceutical.     

Survey of pharmacists’ antibiotic dosing recommendations for sustained low-efficiency dialysis

Background The use of hybrid renal replacement therapies like sustained low efficiency dialysis (SLED) is increasing in ICUs worldwide. However, pharmacokinetic studies designed to inform therapeutic antibiotic dosing in critically ill patients receiving SLED are limited. SLED operational characteristics vary across institutions. Pharmacists in institutions that utilize SLED are challenged to recommend therapeutic doses for antibiotics. Objective To characterize pharmacist-recommended antibiotic regimens for SLED. Methods An electronic survey was sent to pharmacist members of the American College of Clinical Pharmacy in the Nephrology or Critical Care Practice and Research Network. Dosing recommendations for a hypothetical critically ill septic patient were collected for cefepime, ceftaroline, daptomycin, levofloxacin, meropenem, and piperacillin/tazobactam. Main outcome measure Antibiotic regimens for the six antibiotics, their frequency, pharmacist’s experience with renal replacement therapies (RRT), post-graduate training, years of clinical experience, number of staffed beds in their hospital, and RRT employed in their ICUs. Results The survey was completed by 69 clinical pharmacists who had 8.5 ± 7.5 (mean ± SD) years of experience. All pharmacists had experience dosing medications for patients receiving RRT. The most frequently recommended regimen for each antibiotic was: cefepime 1000 mg every 24 h, ceftaroline 200 mg every 12 h, daptomycin 6 mg/kg every 24 h, levofloxacin 500 mg every 24 h, meropenem 1000 mg every 12 h, and piperacillin/tazobactam 2250 mg every 8 h. Up to nine distinct regimens were recommended for each antibiotic, and the total daily dose between these regimens ranged by as much as a 12-fold. Neither pharmacist’s experience with SLED, post-graduate training, nor years of clinical experience were significantly associated with particular dosing recommendations for the antibiotics. Conclusion Pharmacists working in institutions that utilize SLED make antibiotic dosing recommendations that vary 4–12-fold depending on the drug. Published research does not provide adequate guidance to optimally dose antibiotics in patients receiving SLED. More SLED pharmacokinetic trials, real-time serum concentration monitoring and advanced pharmacokinetic modeling techniques are necessary to ensure therapeutic dosing in patients receiving SLED.     

Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7α-APTADD to breast cancer cells

Transferrin (Tf)-conjugated lipid-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles carrying the aromatase inhibitor, 7α-(4′-amino)phenylthio-1,4-androstadiene-3,17-dione (7α-APTADD), were synthesized by a solvent injection method. Formulation parameters including PLGA-to-lipid, egg PC-to-TPGS, and drug-to-PLGA ratios and aqueous-to-organic phase ratio at the point of synthesis were optimized to obtain nanoparticles with desired sizes and drug loading efficiency. The optimal formulation had a drug loading efficiency of 36.3 ± 3.4%, mean diameter of 170.3 ± 7.6 nm and zeta potential of −18.9 ± 1.5 mV. The aromatase inhibition activity of the nanoparticles was evaluated in SKBR-3 breast cancer cells. IC₅₀ value of the Tf-nanoparticles was ranging from 0.77 to 1.21 nM, and IC₅₀ value of the nanoparticles was ranging from 1.90 to 3.41 nM (n = 3). The former is significantly lower than the latter (p < 0.05). These results suggested that the aromatase inhibition activity of the Tf-nanoparticles was enhanced relative to that of the non-targeted nanoparticles, which was attributable to Tf receptor (TfR) mediated uptake. In conclusion, Tf-conjugated lipid-coated PLGA nanoparticles are potential vehicles for improving the efficiency and specificity of therapeutic delivery of aromatase inhibitors.     

Development of enteric submicron particles formulation of α-amylase for oral delivery

Enteric submicron particles (SPs) formulations of α-amylase were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP) and Eudragit L 100, to avoid gastric inactivation of α-amylase. Smaller internal and external aqueous phase volume provided maximum encapsulation efficiency (71.92–73.40%), least particle size (546.4–595.4?nm) and 23–26% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastro-resistance of formulations. The anionic SPs aggregated in 0.1 N HCl (i.e. gastric pH 1.2), due to protonation of carboxylic groups of enteric polymer. The aggregates being < 500 µm size would not impede gastric emptying. However, at pH >5.0 (duodenal pH), SPs showed de-aggregation due to restoration of surface charge. HPMCP and Eudragit L 100 SPs facilitated almost complete release of α-amylase within 30?min at pH 6.0 and 6.8, respectively, following Higuchi kinetics. PXRD and DSC indicated amorphous character and scanning electron microscope showed spherical shape of SPs. In simulated gastro-intestinal pH condition, HPMCP and Eudragit L 100 SPs showed good digestion of cooked rice and could serve as potential carrier for oral enzyme delivery. Stability studies indicated the formulations as quite stable to ensure 2 years shelf life at room temperature.     

Percutaneous delivery of α-melanocyte-stimulating hormone for the treatment of imiquimod-induced psoriasis

Purpose: α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone with anti-inflammatory responses. We developed topical formulation(s) of α-MSH to reduce psoriasis-related inflammation.

Methods: Transcutol (TC) and n-methyl 2-pyrrolidone (NMP) were used to formulate a gel for α-MSH. Skin permeation and dermal microdialysis of the solution and optimized gel were performed. The inflammatory response of α-MSH gel was investigated in imiquimod-induced psoriasis mouse model. Histology and immunohistochemistry were then performed on treated skin.

Results: Solution comprising 50%w/w TC and 10%w/w NMP showed higher (p?<?0.05) skin retention (0.27?±?0.024?µg of α-MSH/mg of skin) than solutions containing either 50% w/w TC or 10% w/w NMP at 24?h. Dispersion of α-MSH in Carbopol Ultrez 10 produced a uniform dispersion. α-MSH gel showed pseudoplastic flow with thixotropic behavior. Dermal microdialysis results suggested that skin permeation of gel after 5?h was 1.9-folds higher than the solution. Further, gel-treated psoriatic-like plaque skin sections showed significant (p?<?0.05) decrease in the expression of a melanocortin receptor, in the psoriasis area and severity index score and transepidermal water loss compared to the solution.

Conclusion: TC, NMP and Carbopol Ultrez 10 form a stable gel with improved skin permeation of α-MSH for a reduction in psoriasis-associated inflammation.     

Is vancomycin redundant for serious staphylococcal infection?

Vancomycin's clinical utility is under serious threat. Intensive use has created selective pressure and many databases record modal minimum inhibitory concentrations (MICs) of ≥1 mg/L. Although the current breakpoint is 2 mg/L this is reasonably well established as having no clinical relevance. Unfortunately, setting a clinical breakpoint of 0.5 or 1 mg/L, which is argued persuasively by the available clinical data, would lead to a loss of reproducibility and frequent misclassification of susceptibility in the laboratory. Moreover, MIC testing is method-dependent and this adds further confusion when trying to ascertain the place of an antibiotic with such a narrow therapeutic window. The optimal pharmacokinetic/pharmacodynamic target of a total area under the curve (AUC)/MIC ratio of 400, although based on only a small number of publications, is backed up by the available clinical studies, albeit that they are non-randomised cohorts, often retrospective. Unfortunately, the toxicity of vancomycin would seem to prevent us from prolonging its useful life by increasing doses. Even if the AUC/MIC ratio 400 were reached, it is not clear that such doses would be more efficacious, as a raised MIC also heralds other changes in the organism, such as altered accessory gene regulation and tolerance, which may further diminish the drug's performance. Unless vancomycin use can be seriously reduced, continued selective pressure is quite likely to lead to further elevations in MICs and increased numbers of strains with intermediate or reduced susceptibility. The same conclusions almost certainly apply to teicoplanin.