When and How to Use MIC in Clinical Practice?

Bacterial resistance to antibiotics continues to be a global public health problem. The choice of the most effective antibiotic and the use of an adapted dose in the initial phase of the infection are essential to limit the emergence of resistance. This will depend on (i) the isolated bacteria and its resistance profile, (ii) the pharmacodynamic (PD) profile of the antibiotic used and its level of toxicity, (iii) the site of infection, and (iv) the pharmacokinetic (PK) profile of the patient. In order to take account of both parameters to optimize the administered treatment, a minimal inhibitory concentration (MIC) determination associated with therapeutic drug monitoring (TDM) and their combined interpretation are required. The objective of this narrative review is thus to suggest microbiological, pharmacological, and/or clinical situations for which this approach could be useful. Regarding the microbiological aspect, such as the detection of antibiotic resistance and its level, the preservation of broad-spectrum β-lactams is particularly discussed. PK-PD profiles are relevant for difficult-to-reach infections and specific populations such as intensive care patients, cystic fibrosis patients, obese, or elderly patients. Finally, MIC and TDM are tools available to clinicians, who should not hesitate to use them to manage their patients

Pharmacokinetic and therapeutic drug monitoring of colistin

La colistine est un antibiotique utilisé en dernier recours dans les infections à bacilles gram négatifs multirésistants. Elle est administrée sous la forme de sa prodrogue, le colistiméthate sodique (CMS). Bien que les données disponibles sur cet antibiotique aient largement augmenté depuis l’apparition des dosages du CMS et de la colistine par méthode séparative couplée à un détecteur, les disparités entre les études perdurent, les mécanismes pharmacocinétiques impliqués ne sont pas tous élucidés et les données manquent quant à l’optimisation de l’utilisation de cet antibiotique.Cette thèse a permis de :1- Vérifier que les dosages de CMS et colistine réalisés dans différents centres européens étaient conformes et homogènes via la réalisation d’une étude de cross-validation multicentrique. 2- Mettre en évidence l’ampleur de la variabilité interindividuelle des concentrations moyennes à l’équilibre en colistine et montrer que cette variabilité était essentiellement due à la clairance de la colistine. 3- Montrer les difficultés de la mise en place d’une optimisation posologique précoce du CMS par analyse bayésienne.4- Evaluer l’impact pharmacocinétique d’une administration du CMS en une seule injection journalière.5- Etudier la pharmacocinétique du CMS et de la colistine après administration par voie intraveineuse et nébulisée de CMS chez les patients souffrant de mucoviscidose. 6- Suggérer une augmentation de la posologie de la colistine en pédiatrie.Ces travaux ont permis d’accroître les connaissances sur la pharmacocinétique de la colistine et de proposer de nouvelles stratégies thérapeutiques afin de contribuer à l’amélioration de la prise en charge des patients.Colistin is an antibiotic used as a last resort in infections caused by multiresistant gram negative bacteria. It is administered as a prodrug, colistin methanesulfonate (CMS). Although data concerning this antibiotic are growing since CMS and colistin quantification is realized by a separative method coupled to a detector, some differences are still present between studies, the pharmacokinetic mechanisms involved are not yet totally elucidatedand there is a lack of data concerning the optimization of its use. In this thesis we:1- Check that CMS and colistin dosages realized in different centers in Europe were compliant and homogenous with a multicentric cross validation study.2- Highlight the inter individual variability of the steady state average concentrations of colistin and show that it is mostly associated to colistin clearance.3- Show the difficulties of an early adaptation of CMS dose regimen by bayesian analysis.4- Evaluate the pharmacokinetic impact of intravenous administration of CMS once daily.5- Study CMS and colistin pharmacokinetic after iv and nebulized administration of CMS in cystic fibrosis patients. 6- Suggest an increase of CMS dosing regimen recommended in children.Overall, this work brings PK understanding of colistin and suggests new therapeutic strategies, particularly in cystic fibrosis patients and in children. This work should contribute to improve patient care in infection caused by multiresistant bacteria

Gentamicin–vancomycin–colistin local antibiotherapy in a cement spacer in a 54-year-old haemophilic patient with relapsing plurimicrobial severe prosthetic joint infection

International audienc

When and How to Use MIC in Clinical Practice?

Bacterial resistance to antibiotics continues to be a global public health problem. The choice of the most effective antibiotic and the use of an adapted dose in the initial phase of the infection are essential to limit the emergence of resistance. This will depend on (i) the isolated bacteria and its resistance profile, (ii) the pharmacodynamic (PD) profile of the antibiotic used and its level of toxicity, (iii) the site of infection, and (iv) the pharmacokinetic (PK) profile of the patient. In order to take account of both parameters to optimize the administered treatment, a minimal inhibitory concentration (MIC) determination associated with therapeutic drug monitoring (TDM) and their combined interpretation are required. The objective of this narrative review is thus to suggest microbiological, pharmacological, and/or clinical situations for which this approach could be useful. Regarding the microbiological aspect, such as the detection of antibiotic resistance and its level, the preservation of broad-spectrum β-lactams is particularly discussed. PK-PD profiles are relevant for difficult-to-reach infections and specific populations such as intensive care patients, cystic fibrosis patients, obese, or elderly patients. Finally, MIC and TDM are tools available to clinicians, who should not hesitate to use them to manage their patients

Clinical Pharmacokinetics and Pharmacodynamics of Colistin

International audienceIn this review, we give an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS) when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin poorly passes through physiological membranes and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin is very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and recently, a plasmid-mediated resistance mechanism (MCR-1) was described in animals and humans. In vitro, when exposed to colistin, bacteria develop various resistance mechanisms rapidly. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary

Clinical Pharmacokinetics and Pharmacodynamics of Colistin

International audienceIn this review, we give an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS) when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin poorly passes through physiological membranes and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin is very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and recently, a plasmid-mediated resistance mechanism (MCR-1) was described in animals and humans. In vitro, when exposed to colistin, bacteria develop various resistance mechanisms rapidly. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary

Pharmacokinetics of colistin after nebulization or intravenous administration of colistin methanesulphonate (Colimycin®) to cystic fibrosis patients

International audienc

Population Pharmacokinetics of Orally Administered Clindamycin to Treat Prosthetic Joint Infections: A Prospective Study

International audienceA population PK model of clindamycin orally administered to patients with prosthetic joint infections (PJIs) was developed using NONMEM 7.5. Monte-Carlo simulations were run to determine the probability of obtaining bone clindamycin concentrations equal to at least the MIC or four times the MIC for several MIC values and dosing regimens. One hundred and forty plasma concentrations prospectively obtained from 20 patients with PJIs were used. A one-compartment model with first-order absorption and elimination appropriately described the data. Mean PK-parameter estimates (F being the bioavailability) were: apparent clearance, CL/F = 23 L/h, apparent distribution volume, V/F = 103 l and absorption rate constant, Ka = 3.53/h, with respective interindividual variabilities (coefficients of variation) of 14.4%, 8.2% and 59.6%. Neither goodness-of-fit curves nor visual predictive checks indicated bias. The currently recommended 600 mg q8h regimen provided a high probability of obtaining concentrations equal to at least the MIC, except for MIC ≥ the clinical breakpoint for Staphylococcus spp. (0.25 mg/L). For such MIC values, higher daily doses and q6h regimens could be considered