Federica Pavan

Pharmacokinetic Considerations for Antimicrobial Therapy in Patients Receiving Renal Replacement Therapy

Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CLCRRT), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CLCRRT of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents.Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CLCRRT may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device’s characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CLCRRT is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distribution and poor plasma protein binding. Consistently, CLCRRT should be clinically relevant particularly for most hydrophilic antimicrobial agents (e.g. β-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which generally are nonrenally cleared. However, there are some notable exceptions: ceftriax-one and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device’s surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied.Conversely, drug removal by means of CVVH or CVVHDF is unaffected by the drug size, considering that almost all antimicrobial agents have molecular weights significantly lower (<2000Da) than the haemofilter cut-off (30 000–50 000Da). Drugs that normally have high renal clearance and that exhibit high CLCRRT during CVVH or CVVHDF may need a significant dosage increase in comparison with renal failure or even IHD. Conversely, drugs that are normally nonrenally cleared and that exhibit very low CLCRRT during CVVH or CVVHDF may need no dosage modification in comparison with normal renal function. Bearing these principles in mind will almost certainly aid the management of antimicrobial therapy in critically ill patients undergoing CRRT, thus containing the risk of inappropriate exposure. However, some peculiar pathophys-iological conditions occurring in critical illness may significantly contribute to further alteration of the pharmacokinetics of antimicrobial agents during CRRT (i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residual renal function). Accordingly, therapeutic drug monitoring should be considered a very helpful tool for optimising drug exposure during CRRT.

Prospectively Validated Dosing Nomograms for Maximizing the Pharmacodynamics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients

ABSTRACT The efficacy of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA)-related infections has been called into question by recent findings of higher rates of failure of vancomycin treatment of infections caused by strains with high MICs. Continuous infusion may be the best way to maximize the time-dependent activity of vancomycin. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CLCr) estimates for use in daily clinical practice to target the steady-state concentrations (Csss) of vancomycin during continuous infusion at 15 to 20 mg/liter (after the administration of an initial loading dose of 15 mg/kg of body weight over 2 h). The correlation between vancomycin clearance (CLv) and CLCr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 70) to create a formula for dosage calculation to target Css at 15 mg/liter. The performance of this formula was prospectively validated in a similar cohort (group 2, n = 63) by comparison of the observed and the predicted Csss. A significant relationship between CLv and CLCr was observed in group 1 (P < 0.001). The application of the calculated formula to vancomycin dosing in group 2 {infusion rate (g/24 h) = [0.029 × CLCr (ml/min) + 0.94] × target Css × (24/1,000)} led to a significant correlation between the observed and the predicted Csss (r = 0.80, P < 0.001). Two dosing nomograms based on CLCr were created to target the vancomycin Css at 15 and 20 mg/liter in critically ill patients. These nomograms could be helpful in improving the vancomycin treatment of MRSA infections, especially in the presence of borderline-susceptible pathogens and/or of pathophysiological conditions which may enhance the clearance of vancomycin, while potentially avoiding the increased risk of nephrotoxicity observed with the use of high intermittent doses of vancomycin.

Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages.

ObjectiveTo define the optimal dosage regimen of teicoplanin that ensures early therapeutically relevant trough concentrations (Cmin) [>10 mg/L at 24 hours and possibly close to 20 mg/L at 48 hours] in patients with acute leukaemia who develop febrile neutropenia after chemotherapy.DesignProspective observational pharmacokinetic study.ParticipantsAdult patients (n = 33) with normal renal function previously treated with antineoplastic chemotherapy because of acute lymphocytic or acute nonlymphocytic leukaemia, and subsequently developing febrile neutropenia treated with empirical antimicrobial therapy.DesignFirst, the standard dosage group (n= 11) was administered standard loading and maintenance doses of teicoplanin (400mg every 12 hours for three doses followed by 400mg once daily). Blood samples were collected at defined times as part of routine monitoring and assessed for teicoplanin plasma concentration by fluorescence polarisation immunoassay. Secondly, the high dosage group (n = 22) received a high loading regimen (800 + 400mg 12 hours apart on day 1, 600 + 400mg 12 hours apart on day 2) followed by a high maintenance regimen (400mg every 12 hours) from day 3 on.ResultsIn the standard dosage group, no patient had the recommended teicoplanin Cmin of ≥10 mg/L within the first 72 hours, and only five of the 11 patients (45%) had a Cmin of ≥10 mg/L after 120 hours. No patient had a Cmin of ≥20 mg/L. In the high dosage group, teicoplanin Cmin averaged ≥10 mg/L within 24 hours, and this value was achieved within 48 hours in all but one patient. Of note, Cmin at 72 hours exceeded 20 mg/L in ten of the 22 patients (45%). No patient experienced significant impairment of renal function.ConclusionsIn this patient group, therapeutically relevant Cmin may be achieved very early in the treatment period with loading doses of 12 mg/kg and 6 mg/kg 12 hours apart on day 1, and 9 mg/kg and 6 mg/kg 12 hours apart on day 2, regardless of renal function. Subsequently, in patients with normal renal function a maintenance dosage of 6 mg/kg every 12 hours may be helpful in ensuring Cmin close to 20 mg/L. Assessment of Cmin after 48–72 hours may be useful to individualise teicoplanin therapy. Factors increasing volume of distribution and/or renal clearance of teicoplanin (fluid load, hypoalbuminaemia, leukaemic status) may explain the need for higher dosages.

Hyperlactacidemia Potentially Due to Linezolid Overexposure in a Liver Transplant Recipient

Sir—A 59-year-old white liver transplant recipient developed bilateral pneumonia on day 4 after the operation. After performing bronchoscopy with bronchoalveolar lavage, empirical therapy with piperacillin-tazobactam (4.5 g every 6 h) and levofloxacin (500 mg every 12 h) was commenced. During the subsequent 24 h, the patient’s clinical condition worsened until he developed severe sepsis. Drotrecogin-a was administered, but because of the persistence of the patient’s critical condition, and because no bacteria were isolated, antibiotic therapy was shifted 48 h later to meropenem (500 mg every 6 h) plus linezolid (600 mg every 12 h). Over the subsequent days, the patient’s clinical condition slowly improved. However, despite there being no evidence of graft dysfunction or renal failure, a progressive asymptomatic increase in the plasma lactate level was noted (peak level, 8.4 mmol/L) (figure 1). On day 10 of the second-line antibiotic regimen, therapy was de-escalated by withdrawing meropenem. In accordance with our institution’s antibiotic policy, which is oriented at optimizing therapy for critically ill patients [1], multiple blood samples were obtained to assess linezolid exposure during a dosing interval and were subsequentlyanalyzed by high-performance liquid chromatography [2]. Pharmacokinetic analysis revealed significant plasma overexposure to linezolid (12-h area under the curve, 412.55 /L; maximum concentration, 43.32 mg h mg/L; minimum concentration, 26.99 mg/ L) because of impaired clearance (1.51 L/ h) with a prolonged elimination half-life (16.57 h) [3]. We hypothesized that the patient potentially had drug-induced hyperlactacidemia. On day 12 of hospitalization, linezolid was withdrawn, and blood samples were obtained to determine whether plasma drug levels were decreasing. During the subsequent 2 days, concomitantly with a decrease in the plasma linezolid level, a progressive decrease of the plasma lactate level (until complete normalization occurred) was documented (figure 1). Hyperlacticidemia during linezolid therapy has been previously reported to be an adverse event that mainly develops after long treatment periods and that slowly resolves after withdrawal of the drug [4–6]. Conversely, in the case we report, lactate levels started increasing just after the first week of treatment, rapidly achieved the maximum level, and returned to a normal level within 48 h after drug withdrawal. It has been suggested that, on the basis of its mechanism of action, linezolid may cause hyperlacticidemia by inhibiting mitochondrial protein synthesis [6]. Therefore, hyperlacticidemia should be expected to occur earlier in the course of treatment and to be more severe in patients who

Levofloxacin Disposition in Cerebrospinal Fluid in Patients with External Ventriculostomy

ABSTRACT In vitro levofloxacin exhibits both potent or intermediate activity against most of the pathogens frequently responsible for acute bacterial meningitis and synergistic activity with some beta-lactams. Since levofloxacin was shown to penetrate the cerebrospinal fluid (CSF) during meningeal inflammation both in animals and in humans, the disposition of levofloxacin in CSF was studied in 10 inpatients with external ventriculostomy because of communicating hydrocephalus related to subarachnoid occlusion due to cerebral accidents who were treated with 500 mg of levofloxacin intravenously twice a day because of extracerebral infections. Plasma and CSF concentration-time profiles and pharmacokinetics were assessed at steady state. Plasma and CSF levofloxacin concentrations were analyzed by high-pressure liquid chromatography. The peak concentration of levofloxacin at steady state (Cmax ss)was 10.45 mg/liter in plasma and 4.06 mg/liter in CSF, respectively, with the ratio of the Cmax ss in CSF to the Cmax ss in plasma being 0.47. The areas under the concentration-time curves during the 12-h dosing interval (AUC0-τs) were 47.69 mg · h/liter for plasma and 33.42 mg · h/liter for CSF, with the ratio of the AUC0-τ for CSF to the AUC0-τ for plasma being 0.71. The terminal-phase half-life of levofloxacin in CSF was longer than that in plasma (7.02 ± 1.57 and 5.51 ± 1.36 h, respectively; P = 0.034). The ratio of the levofloxacin concentration in CSF to the concentration in plasma progressively increased with time, from 0.30 immediately after dosing to 0.99 at the end of the dosing interval. In the ventricular CSF of patients with uninflamed meninges, levofloxacin was shown to provide optimal exposure, which approximately corresponded to the level of exposure of the unbound drug in plasma. The findings provide support for trials of levofloxacin with twice-daily dosing in combination with a reference beta-lactam for the treatment of bacterial meningitis in adults. This cotreatment could be useful both for overcoming Streptococcus pneumoniae resistance and for enabling optimal exposure of the CSF to at least one antibacterial agent for the overall treatment period.

Ceftazidime in Acute Myeloid Leukemia Patients with Febrile Neutropenia: Helpfulness of Continuous Intravenous Infusion in Maximizing Pharmacodynamic Exposure

ABSTRACT The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion of ceftazidime was assessed in 20 febrile neutropenic patients with acute myeloid leukemia. Mean steady-state ceftazidime concentrations averaging 40 mg/liter from day 2 on ensured maximized pharmacodynamic exposure (values close to four to five times the MIC breakpoint against Pseudomonas aeruginosa). However, large intra- and interindividual pharmacokinetic variability was documented throughout the study period.

Treatment of pyogenic (non-tuberculous) spondylodiscitis with tailored high-dose levofloxacin plus rifampicin

The purpose of this study was to assess the clinical efficacy of high-dose levofloxacin plus rifampicin in the empirical treatment of non-tuberculous spondylodiscitis in an epidemiological context of low incidence of staphylococcal fluoroquinolone resistance. All consecutive adult patients with spondylodiscitis (January 2003 to December 2006) were empirically treated with high-dose levofloxacin (500 mg every 12 h normalised to renal function and optimised by means of therapeutic drug monitoring whenever feasible) plus rifampicin 600 mg every 24 h. Trough and peak plasma concentrations were targeted at 1-3 mg/L and 6-9 mg/L, respectively, to maximise the concentration-dependent activity of levofloxacin in bone. Follow-up was performed until 9 months after the end of therapy. Forty-eight patients were included. Eleven patients underwent a surgical approach for spine stabilisation. Among the 29 bacterial isolates, Staphylococcus aureus was the most frequent (65.5%) (all meticillin-susceptible strains). Tailored levofloxacin plasma exposure over time was ensured in most cases. Median treatment duration was 15.1 weeks. Overall response rates were: 77.1% at the intent-to-treat analysis; 84.1% among patients who completed therapy (N=44); and 96.3% among those receiving targeted therapy against documented levofloxacin-susceptible isolates (N=27). No patient had evidence of disease relapse at follow-up. Our findings suggest that high-dose levofloxacin regimens may be highly effective in the treatment of non-tuberculous spondylodiscitis and support its putative role in combination with rifampicin against S. aureus.

Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients.

Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (β-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur.

Pharmacokinetic and Pharmacodynamic Aspects of Oral Moxifloxacin 400 mg/day in Elderly Patients with Acute Exacerbation of Chronic Bronchitis

ObjectiveTo assess the pharmacokinetic and pharmacodynamic behaviour of moxifloxacin in 15 consecutive elderly patients with acute exacerbation of chronic bronchitis (AECB) treated with the fixed oral moxifloxacin 400 mg/day regimen with the intent of verifying which degree of exposure may be ensured by this standard regimen against AECB pathogens.MethodsThis was an open-label, observational, pharmacokinetic-pharmacodynamic study. Blood samples were collected at steady state at appropriate intervals. Moxifloxacin plasma concentrations were analysed by means of high-performance liquid chromatography. Standard pharmacokinetic parameters and pharmacodynamic determinants (peak concentration [Cmax]/minimum inhibitory concentration [MIC], area under the plasma concentration-time curve during the 24-hour observational period [AUC24]/MIC, pharmacodynamic breakpoints [PDBPs]) were assessed.ResultsThe mean estimated pharmacokinetic parameters (Cmax 4.40 mg/L at 1.4 hours, AUC24 42.67 mg ′ h/L, elimination half-life 12.55 hours, total body clearance 0.16 L/h/kg) were generally similar to those observed in both young and elderly historic controls (except for higher-dose normalised Cmax and lower volume of distribution of the central compartment). Median Cmax/MIC and AUC24/MIC ratios for moxifloxacin in the fully assessable cases were, respectively, 67.5 and 823.9 against Streptococcus pneumoniae, 25 and 310.2 against Moraxella catharralis and 416.5 and 3647.5 against Haemophilus influenzae. Mean estimates of PDBP for achieving Cmax/MIC values of 12.2 and AUC24/MIC values of 125 were 0.36 and 0.35 mg/L, respectively.ConclusionIn patients with AECB the pharmacokinetic behaviour of moxifloxacin is not significantly altered by aging processes. This is consistent with moxifloxacin being metabolised mainly by means of phase II hepatic reactions, the activity of which was shown not to decline with age. Both the pharmacokinetic and pharmacodynamic analyses suggest that moxifloxacin 400 mg/day may be a valid therapeutic approach in the treatment of AECB in the elderly. Of note, the unmodified pharmacokinetic behaviour with no need for age-related dosage adjustments combined with the once-daily administration favouring compliance and the low potential for drug-drug pharmacokinetic interactions in case of polytherapy, make moxifloxacin particularly attractive in the treatment of elderly subpopulations at a very high risk of AECB.

Levofloxacin disposition over time in aqueous humor of patients undergoing cataract surgery

ABSTRACT The ocular disposition of levofloxacin in patients receiving two 500-mg oral doses 10 h apart before cataract surgery was assessed with the intent of defining drug ocular exposure over time. The mean aqueous humor concentrations persisted above 1.5 mg/liter between 1.5 and 6.0 h after the second dose, with average aqueous-to-plasma ratios ranging between 0.33 and 0.57. This favorable ocular disposition provides support for trials of systemic levofloxacin for prophylaxis of postoperative endophthalmitis in selected patients or as adjunctive therapy for the treatment of this potentially devastating infective complication.