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•Treatment options for MRSA among different types of infections are described.•Vancomycin remains a possible, but patient-tailored, option.•New lipoglycopeptides and third-generation cephalosporins have good potency and efficacy.•Tedizolid is an attractive agent for use both in hospital and community settings.•More data from clinical practice are needed to assign specific roles to each antibiotic.

ABSTRACTTeicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h−1(8.16 h−1); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h−1(8.93 h−1). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations.IMPORTANCE(This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.)

SummaryFluoroquinolones are a class of antibiotics that are widely used in the treatment of a number of severe infections frequently observed in intensive care units (ICU). From a pharmacodynamic point of view, the optimal conditions for guaranteeing clinical recovery and preventing the occurrence of resistance to this class of antibiotics are represented by the ratios of Cmax/MIC >12.2 and AUC24h/MIC equal to 100–125 hours for Gram-negative bacteria, and about 30-40 hours for Gram-positive cocci. Taking this into consideration, the pharmacokinetics and pharmacodynamics shown in healthy volunteers suggest that with the use of standard doses of the various fluoroquinolones, an optimal AUCfree/MIC ratio for Gram-negative bacteria may be ensured with a minimum inhibitory concentration (MIC) <0.25–0.5 mg/L and for Gram-positive bacteria with an MIC <0.5–1 mg/L. The need to increase the dosage, or to combine them with other antibiotics is therefore recognized, when it is necessary to ensure adequate coverage of intermediately sensitive microorganisms (MIC 1–2 mg/L). In addition, patients recovered in the ICU often present some peculiar pathophysiological conditions that increase the distribution volume and/or the renal clearance of the drug. Thus it is likely that in this situation it would be reasonable to increase daily dosages, independent of the in vitro pattern of drug sensitivity (e.g. 500 mg b.i.d. for levofloxacin).Data from various clinical and pharmacological studies suggesting a potential role for fluoroquinolones both in monotherapy and combination therapy in the treatment of different clinically severe conditions are presented and discussed. This offers the dual opportunity to evaluate the role of quinolones as an alternative to aminoglycosides in combination with a beta-lactam and, at the same time, to consider their use in a periodic rotation program of anti-Gram-negative antibiotic therapy when there is a high risk of resistance selection, such as in the ICU. In conclusion, the role of fluoroquinolones in the treatment of multiple infectious diseases, such as bacteremia/sepsis, pneumonia and severe urinary tract infections in an environment such as the ICU is growing stronger, while there are convincing data indicating that these molecules might play a role in the treatment of meningitis in the near future.

RiassuntoI fluorochinoloni rappresentano una classe di antibiotici largamente utilizzata nel trattamento di numerose patologie infettive gravi di frequente osservazione in ambito intensivistico (UTI). Da un punto di vista farmacodinamico, condizioni ottimali per garantire la guarigione clinica e prevenire l’insorgenza di resistenze verso tale classe di antibiotici sono rappresentate da rapporti Cmax/MIC > 12,2 e rapporti AUC24h/MIC pari a 100-125 ore, per i batteri Gram negativi, e verosimilmente pari a 30-40 ore per i cocchi Gram positivi. In considerazione di ciò, i dati farmacocinetici e farmacodinamici rilevati nel volontario sano suggeriscono che con le dosi standard dei vari fluorochinoloni si possa garantire un rapporto AUClibera/MIC ottimale soltanto per batteri Gram negativi con MIC < 0,25-0,5 mg/L e per batteri Gram positivi con MIC < 0,5-1 mg/L. Si deduce pertanto la necessità di ricorrere ad aumento della posologia, ovvero a schemi di terapia di combinazione con altri antibiotici, quando sia necessario garantire un’adeguata esposizione nei confronti di microrganismi a sensibilità intermedia (MIC 1-2 mg/L). Inoltre, i pazienti ricoverati in UTI presentano spesso alcune peculiarità fisiopatologiche, quali aumentato volume di distribuzione dei farmaci e/o aumentata clearance renale, per cui è verosimile che in tale contest siano razionali dosaggi giornalieri più elevati indipendentemente dal pattern di chemiosensibilità dell’isolato (es. 500 mg bid per levofloxacina).Vengono presentati e discussi i dati relativi a vari studi clinici e farmacologicoclinici che suggeriscono un potenziale ruolo per i fluorochinoloni, sia in monoterapia che in terapia di associazione, nel trattamento di differenti condizioni cliniche gravi. Ciò offre la duplice opportunità di valutare il ruolo dei chinoloni quale alternativa agli aminoglicosidi in associazione ai betalattamici in terapie di combinazione ed al contempo di considerane l’utilizzo in programmi di rotazione periodica della terapia antibiotica anti-Gram-negativi in contesti a particolare rischio di selezione di resistenze quali le UTI. In conclusione, il ruolo dei fluorochinoloni in ambito intensivistico si va progressivamente consolidando nel trattamento di multiple condizioni patologiche quali batteriemia/sepsi, polmonite e infezioni gravi delle vie urinarie, mentre vi sono dati convincenti per supporre che nel prossimo futuro tali molecole possano ritagliarsi uno spazio rilevante anche nel trattamento delle meningiti.

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14 ± 0.4mgkg−1body weight) of CsA-SCG. The steady-state area under the concentration–time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in Cmaxss( 732 ± 178 vs935 ± 250 ng ml−1, P< 0.001) and tmax( 2.63 ± 1.21 vs1.36 ± 0.49 h, P< 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG ( 75 ± 19 vs66 ± 16%;P< 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations.

The aim of this study was to evaluate retrospectively the importance of a Bayesian pharmacokinetic approach for predicting vancomycin concentrations to individualize its dosing regimen in 18 critically ill patients admitted to intensive care units following cardiothoracic surgery. The possible influence of some coadministered drugs with important haemodynamic effects (dopamine, dobutamine, frusemide) on vancomycin pharmacokinetics was assessed. Vancomycin serum concentrations were measured by fluorescence polarization immunoassay. Vancomycin dosage regimens predicted by the Bayesian method (D(a)) were compared retrospectively with Moellering's nomogram-based dosages (D(M)) to assess possible major differences in vancomycin dosing. D(a) values were similar to D(M) in 10 patients (D(a) approximately D(M) group) (20.52 +/- 8.40 mg/kg/day versus 18.81 +/- 7.24 mg/kg; P = 0.15), whereas much higher dosages were required in the other eight patients (D(a) >> D(M) group) (26.78 +/- 3.01 mg/kg/day versus 18.95 +/- 3.41 mg/kg/day; P < 0.0001) despite no major difference in attained vancomycin steady-state trough concentration (C(min ss)) (9.22 +/- 1. 33 mg/L versus 8.99 +/- 1.26 mg/L; = 0.75) or estimated creatinine clearance (1.23 +/- 0.49 mL/min/kg versus 1.21 +/- 0.24 mL/min/kg; P = 0.95) being found between the two groups. The ratio between D(a) and D(M) was significantly higher in the D(a) >> D(M) group than in the D(a) approximately D(M) group (1.44 +/- 0.18 versus 1.10 +/- 0. 21; P < 0.01). In four D(a) >> D(M) patients the withdrawal of cotreatment with haemodynamically active drugs was followed by a sudden substantial increase in the vancomycin C(min ss) (13.30 +/- 1. 13 mg/L versus 8.79 +/- 0.87 mg/L; P < 0.01), despite no major change in bodyweight or estimated creatinine clearance being observed. We postulate that these drugs with important haemodynamic effects may enhance vancomycin clearance by inducing an improvement in cardiac output and/or renal blood flow, and/or by interacting with the renal anion transport system, and thus by causing an increased glomerular filtration rate and renal tubular secretion. Given the wide simultaneous use of vancomycin and dopamine and/or dobutamine and/or frusemide in patients admitted to intensive care units, clinicians must be aware of possible subtherapeutic serum vancomycin concentrations when these drugs are coadministered. Therefore, therapeutic drug monitoring (TDM) for the pharmacokinetic optimization of vancomycin therapy is strongly recommended in these situations.

To evaluate the effects of a 6-month methotrexate (MTX) treatment period on cyclosporine A (CsA) pharmacokinetics were subsequently added in patients with rheumatoid arthritis (RA) in comparison with patients treated with CsA only, CsA was administered to 30 subjects with RA (group A) treated with MTX (10 mg week−1i.m.) for 6 months and to 30 patients (group B) who received no MTX treatment. The mean doses±SD of CsA used in groups A and B were 3.2±0.5 and 3.3±0.4 mg kg−1, respectively. CsA levels were determined in whole blood by means of a fluorescence polarization immunoassay (FPIA) method with a specific monoclonal antibody. The following pharmacokinetics parameters were calculated: area under the curve from 0 to 24 h (AUC0–24), half-life of the elimination phase (T1/2β), total body clearance CL·F−1; V·F−1and apparent volume of distribution (Vdβ). The mean blood concentrations and the pharmacokinetic parameters calculated in group A did not present significant statistical differences in comparison to group B. In conclusion, a 6-month MTX therapy does not produce liver function modifications to such an extent as to modify the pharmacokinetics of CsA subsequently added. Therefore, from a clinical pharmacological point of view, an MTX-CsA cotreatment appears feasible.pc 1999 Academic Press@p$hr

Abstract: Objective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h−1 · m−2 vs 139.65 (69.45) l · h−1 · m−2; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l−1 vs 2896.60 (736.38) μg · h · l−1; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. Conclusion: The results show that CyA alone at a dose of 10 mg · kg−1 daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered.

Cyclosporine (CsA) and some of its metabolites (M9, M17, M18, M21) have been determined by means of an LC-MASS method in eight psoriatic patients developing nephrotoxicity. In comparison with a control group (15 psoriatics who after the same period of time, with the same daily dose, did not develop nephrotoxicity) they showed an increase of CsA metabolites, especially M17. Because M17 blood concentrations in the nephrotoxic group tended to be higher than in the control group from the first week of treatment we suggest that M17 might be considered a marker of ongoing nephrotoxicity.

We have studied whether the prediction of drug concentrations improves as the number of samples used for individualization is increased, and whether the Bayesian method of individualization is superior to the non-linear least-squares method. Data were obtained from ten adult haematological patients with multidrug resistance who were treated with cyclosporin. The predictions of blood–cyclosporin concentrations were made using the Abbott PKS program. The number of samples used for individualization was increased from 1 to 30 for the Bayesian method and from 4 to 30 for the non-linear least-squares method. Linear regression, percentage prediction error, and absolute and relative predictive performance were used to evaluate the predictions.The results show that the Bayesian method affords greater precision than the non-linear least-squares method, but that the non-linear least-squares method is more accurate and results in less bias. Whereas for linear regression predictions improve as the number of samples is increased, other evaluations show improvement in the range from 5 to 11 samples; linear regression, percentage prediction errors and prediction bias support the opinion that the Bayesian method progressively becomes the non-linear least-squares method as the number of samples used for individualization is increased, but the accuracy and precision of prediction do not support this opinion.The study supports the statement that Bayes’ law requires parameters from an infinite population, otherwise the advantage of the Bayesian method might be marginal.

We have studied whether the prediction of drug concentrations improves as the number of samples used for individualization is increased, and whether the Bayesian method of individualization is superior to the non‐linear least‐squares method. Data were obtained from ten adult haematological patients with multidrug resistance who were treated with cyclosporin. The predictions of blood–cyclosporin concentrations were made using the Abbott PKS program. The number of samples used for individualization was increased from 1 to 30 for the Bayesian method and from 4 to 30 for the non‐linear least‐squares method. Linear regression, percentage prediction error, and absolute and relative predictive performance were used to evaluate the predictions.

Since motor fluctuations in Parkinsonian patients might be, at least in part, explained by an antagonism between levodopa (LD) and its metabolite 3-O-methyldopa (3-OMD) at blood-brain-barrier (BBB), we decided to study LD and 3-OMD plasma and cerebrospinal fluid (CSF) levels in subjects undergoing lumbar puncture for diagnostic purposes. After informed consent, 70 subjects took a tablet of carbidopa-levodopa association (Sinemet or Sinemet-CR) 0.5, 1, 2, 4, 8, 12h before blood and lumbar cerebrospinal fluid collection. LD and 3-OMD were determined by an HPLC-electrochemical method. The subjects treated with Sinemet-CR had lower LD cerebrospinal fluid concentrations along with lower LD and higher 3-OMD plasma concentrations. This pattern of LD cerebrospinal fluid concentrations may be explained by means of a transport competition between LD and 3-OMD at blood brain barrier level.

Bacterial infection is a very common complication in hematological neutropenic patients whose treatment is extremely challenging for several reasons. First, they are frequently caused by resistant pathogens (multidrug resistant (MDR)), and this may limit the availability of effective therapeutic weapons. Second, these patients often present peculiar pathophysiological conditions that may alter the pharmacokinetic behavior of antimicrobials, and this may explain the need for a new administration schedule and new dosing regimens of antibiotics in this setting. In an era in which there are only few new therapeutic weapons for the treatment of MDR bacterial infections, while advocating for new drugs, what could be effectively done nowadays is to increase the knowledge on appropriateness of the use of currently available drugs to improve clinical outcome and to preserve their activity.