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Federico Pea

Publications and source records attributed to Federico Pea.

At least 19 recordsLinked to original sources
PubMed2006

Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose.

Respiratory fluoroquinolones are currently considered by several guidelines among the most effective antimicrobial agents for the treatment of acute bacterial rhinosinusitis. The aim of this study was to assess levofloxacin penetration into paranasal sinuses mucosa of 15 patients with chronic rhinosinusitis 1h (n = 4), 2 h (n = 5) and 3 h (n = 6) after a single 500 mg oral dose. Levofloxacin concentrations in plasma and tissue samples were assessed by means of HPLC. Median of mucosal concentrations were 0.96 mg l(-1) at 1 h, 2.50 mg l(-1) at 2 h, 5.84 mg l(-1) at 3 h. Average paranasal sinuses mucosa-to-plasma ratios raised from 1.46 at 1 h, to 1.81 at 2 h and to 2.56 at 3 h. These data are consistent with 500 mg oral levofloxacin ensuring appropriate therapeutic exposure in sinonasal tissue of patients with chronic rhinosinusitis, the concentrations between 1 and 3 h post-dosing being almost always higher than the MIC90 against the major bacterial pathogens responsible for upper respiratory tract infections.

Adult↗
PubMed2006

Which reliable pharmacodynamic breakpoint should be advised for ciprofloxacin monotherapy in the hospital setting? A TDM-based retrospective perspective.

OBJECTIVES: To define in critically ill patients receiving intravenous (iv) ciprofloxacin (200 mg or 400 mg twice daily) and undergoing routine therapeutic drug monitoring (TDM) the interindividual pharmacokinetic variability and the reliable pharmacodynamic breakpoint enabled by these fixed dosing regimens according to the PK/PD principles and to the pattern of susceptibility to this antibiotic. METHODS: Ciprofloxacin plasma concentrations [trough (Cmin) and 30 min post-dose peak (Cmax) levels] were analysed by means of an HPLC method. Optimal pharmacodynamic exposure was assessed by estimating the theoretical pharmacodynamic breakpoints (PD BP) for either Cmax or AUC. RESULTS: The final database included 177 sets of Cmin and Cmax performed in 89 patients (200 mg twice daily group, n=68; 400 mg twice daily group, n=21). A very wide interindividual scatter of results was observed for both the 200 mg group and the 400 mg group. Interestingly, for both groups only moderate log-linear relationships between estimated renal function (CLCR) on one hand and either Cmin (r2=0.08, 0.28) or estimated AUC24 (r2=0.10, 0.34) on the other hand were found. Median PD BP, respectively, in the 200 mg twice daily group and the 400 mg twice daily group, were 0.16 and 0.28 mg/L for Cmax, and 0.19 and 0.29 mg/L for AUC24. CONCLUSIONS: Lowering ciprofloxacin dosage in the presence of renal failure seems in most cases unnecessary, since drug accumulation occurred only in a few cases. Optimal pharmacodynamic exposure with fixed 200 or 400 mg twice daily regimens of ciprofloxacin may be ensured only against fully susceptible microorganisms with an MIC<0.3 mg/L. This supports the use of higher dosages in critically ill hospitalized patients, whereas the wide unpredictable interindividual pharmacokinetic variability suggests the usefulness of TDM with the intent of optimizing efficacy with ciprofloxacin therapy.

Analysis of Variance↗
PubMed2006

The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients?

Until recently, the in vitro susceptibility of microorganisms was considered the only fundamental aspect for antibiotic efficacy in treating pneumonia. However, the relevance of pharmacokinetic-pharmacodynamic relationships in optimizing drug exposure has been progressively highlighted. Antimicrobial agents were divided into concentration-dependent or time-dependent groups, with the most consistently relevant pharmacodynamic parameters for efficacy being either the ration of the plasma peak concentration to the minimum inhibitory concentration or the time the plasma concentration persists above the minimum inhibitory concentration of the etiological agent, respectively. For the adequate treatment of pneumonia, optimal pharmacodynamic exposure should be ensured also at the infection site. To investigate this, a methodologically correct approach may be to detect drug concentration levels in the epithelial lining fluid and in the alveolar macrophages for extracellular and intracellular pathogens, respectively. From this perspective, the pharmacokinetic factors--only in some instances--support the achievement of optimal exposure during the treatment of pneumonia with fixed standard dosing regimens of antimicrobials; conversely, in other instances, the pharmacokinetic factors suggest the need for an implemented dosage regimen or even the choice of a different drug.

Anti-Bacterial Agents↗
PubMed2006

The effect of multifactorial, multidisciplinary educational interventions on appropriate use of teicoplanin.

The aim of this study was to determine the effect of multifactorial, multidisciplinary educational interventions over a 3-year period on the appropriate use of teicoplanin. Teicoplanin was considered a valid surrogate marker of good antibiotic use in clinical practice owing to its peculiar pharmacokinetics (i.e. necessity for an initial loading dose regardless of the patient's renal function for early achievement of optimal exposure, namely C(min) > or = 10 mg/L) and to the opportunity of comparing current routine therapeutic drug monitoring (TDM) results with those of a historical retrospective study. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study, both when considered as a whole (66.6% versus 38.6%, respectively; P<0.001) or when stratified according to the degree of estimated renal function (78.4% versus 60.4% for creatinine clearance (CL(Cr)) > 50 mL/min; 59.8% versus 26.8% for CL(Cr) 20-50 mL/min; and 27.7% versus 5.5% for CL(Cr) <20 mL/min). The highest adherence was observed in haematological wards (97.7%). The percentages of patients with teicoplanin C(min) > or = 10 mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. Our findings suggest that continuous application of a multifactorial educational programme including active TDM may be efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin.

Aged↗
PubMed2006

Pharmacokinetic and pharmacodynamic aspects of oral moxifloxacin 400 mg/day in elderly patients with acute exacerbation of chronic bronchitis.

OBJECTIVE: To 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. METHODS: This 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 [C(max)]/minimum inhibitory concentration [MIC], area under the plasma concentration-time curve during the 24-hour observational period [AUC(24)]/MIC, pharmacodynamic breakpoints [PDBPs]) were assessed. RESULTS: The mean estimated pharmacokinetic parameters (C(max) 4.40 mg/L at 1.4 hours, AUC(24) 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 C(max) and lower volume of distribution of the central compartment). Median C(max)/MIC and AUC(24)/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 C(max)/MIC values of 12.2 and AUC(24)/MIC values of 125 were 0.36 and 0.35 mg/L, respectively. CONCLUSION: In 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.

Aged↗
PubMed2005

Pharmacokinetic-pharmacodynamic aspects of antimicrobial prophylaxis with teicoplanin in patients undergoing major vascular surgery.

A prospective, two-arm, open study assessing plasma exposure to teicoplanin with two different prophylactic regimens (Group A (n = 23), 800 mg pre-operatively versus Group B (n = 24), 400 mg pre-operatively plus two doses of 200 mg 24 h apart) was carried out in patients undergoing major vascular surgery. The intent was to define the feasibility and the possible advantages of the single pre-operative high dose in ensuring therapeutically effective plasma concentrations (>10 mg/L) of teicoplanin even during long-lasting operations. At the end of the intervention, mean teicoplanin concentrations (+/-S.D.) were 14.05 +/- 5.13 mg/L and 5.39 +/- 2.13 mg/L in Groups A and B, respectively. At 24 h, average teicoplanin levels were 5.10 +/- 1.25 mg/L and 2.08 +/- 0.73 mg/L in Groups A and B, respectively; at 48 h they declined to 2.86 +/- 0.70 mg/L in Group A, whereas they rose to 2.67 +/- 0.82 mg/L after administration of 2.63 +/- 0.51 mg/kg at 24 h in Group B. Single pre-operative high-dose teicoplanin may ensure effective plasma levels even in cases of very long-lasting operations (>8 h) with no need for intraoperative re-dosing and may enable more appropriate prophylactic exposure than that achievable with the same total dose given in three administrations 24 h apart.

Aged↗
PubMed2005

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

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.

Aged↗
PubMed2005

Ceftazidime in acute myeloid leukemia patients with febrile neutropenia: helpfulness of continuous intravenous infusion in maximizing pharmacodynamic exposure.

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.

Adult↗
PubMed2005

Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability.

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients. Selecting the appropriate antimicrobial at the commencement of therapy, both in terms of spectrum of activity and dose and frequency of administration according to concentration or time dependency, is mandatory in this setting. Despite appropriate standard dosage regimens, failure of the antimicrobial treatment may occur because of the inability of the antimicrobial to achieve adequate concentrations at the infection site through alterations in its pharmacokinetics due to underlying pathophysiological conditions. According to the intrinsic chemicophysical properties of antimicrobials, hydrophilic antimicrobials (beta-lactams, aminoglycosides, glycopeptides) have to be considered at much higher risk of inter- and intraindividual pharmacokinetic variations than lipophilic antimicrobials (macrolides, fluoroquinolones, tetracyclines, chloramphenicol, rifampicin [rifampin]) in critically ill patients, with significant frequent fluctuations of plasma concentrations that may require significant dosage adjustments. For example, underexposure may occur because of increased volume of distribution (as a result of oedema in sepsis and trauma, pleural effusion, ascites, mediastinitis, fluid therapy or indwelling post-surgical drainage) and/or enhanced renal clearance (as a result of burns, drug abuse, hyperdynamic conditions during sepsis, acute leukaemia or use of haemodynamically active drugs). On the other hand, overexposure may occur because of a drop in renal clearance caused by renal impairment. Care with all these factors whenever choosing an antimicrobial may substantially improve the outcome of antimicrobial therapy in critically ill patients. However, since these situations may often coexist in the same patient and pharmacokinetic variability may be unpredictable, the antimicrobial policy may further benefit from real-time application of therapeutic drug monitoring, since this practice, by tailoring exposure to the individual patient, may consequently be helpful both in improving the outcome of antimicrobial therapy and in containing the spread of resistance in the hospital setting.

Anti-Infective Agents↗
PubMed2004

Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: a report of 2 cases.

Linezolid is a new oxazolidinone antibiotic active against most Gram-positive microorganisms the renal elimination of which accounts for about 30% to 35% of all the clearance. Its pharmacokinetic ability was assessed during continuous venovenous hemofiltration (CVVH) in 2 anuric patients with severe postsurgical intraabdominal infections who were receiving standard dosages (600 mg intravenously twice a day). Blood samples for quantification of linezolid in plasma and in filtrate were collected after more than 4 days of therapy before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning 1-hour intravenous infusion, and concentrations were determined by means of high-performance liquid chromatography. Linezolid was partially cleared by CVVH in both the patients (hemofiltration clearance [CL CVVH ] = 0.38 and 0.35 mL/min/kg), with high sieving coefficient values (0.76 to 0.92). Efficacious plasma exposure for time-dependent antibacterial activity of linezolid, either in terms of trough levels above minimum inhibitory concentration (MIC) at which 90% of the isolates are inhibited (Cmin >MIC90 ) or of area under the plasma concentration time curve to MIC90 ratio (AUC/MIC90 ) >100 hours, was ensured during CVVH in both patients. However, despite similar CL CVVH , significant interindividual pharmacokinetic variability was found in the 2 patients (AUC during the observational period [AUC 0-tau ] 334.71 versus 109.34 mg/L x h), mainly owing to substantial differences in non-CVVH-related clearance of linezolid (total CL, 0.55 versus 1.21 mL/min/kg). Our findings indicate that linezolid, although partially removed, does not warrant dosage modification during the first 48 hours when CVVH (with polysulfide hemofilter) at standard 2,000 mL/h substitution flow rate in predilution is applied to anuric patients. Thereafter, this choice is a reasonable one with the exception of those patients who have other features of linezolid toxicity and in which non-CVVH-related clearance might be impaired, although further evaluations are warranted.

Acetamides↗
PubMed2004

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

OBJECTIVE: To define the optimal dosage regimen of teicoplanin that ensures early therapeutically relevant trough concentrations (C(min)) [>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. DESIGN: Prospective observational pharmacokinetic study. PARTICIPANTS: Adult 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. DESIGN: First, the standard dosage group (n = 11) was administered standard loading and maintenance doses of teicoplanin (400 mg every 12 hours for three doses followed by 400 mg 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 + 400 mg 12 hours apart on day 1, 600 + 400mg 12 hours apart on day 2) followed by a high maintenance regimen (400 mg every 12 hours) from day 3 on. RESULTS: In the standard dosage group, no patient had the recommended teicoplanin C(min) of >or=10 mg/L within the first 72 hours, and only five of the 11 patients (45%) had a C(min) of >or=10 mg/L after 120 hours. No patient had a C(min) of >or=20 mg/L. In the high dosage group, teicoplanin C(min) averaged >or=10 mg/L within 24 hours, and this value was achieved within 48 hours in all but one patient. Of note, C(min) at 72 hours exceeded 20 mg/L in ten of the 22 patients (45%). No patient experienced significant impairment of renal function. CONCLUSIONS: In this patient group, therapeutically relevant C(min) 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 C(min) close to 20 mg/L. Assessment of C(min) 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.

Adult↗
PubMed2003

Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing the importance of a loading dose.

Data obtained as part of our routine drug monitoring of teicoplanin therapy (therapeutic drug monitoring, TDM) in adult critically ill patients being treated for suspected or documented Gram-positive multiresistant infections were assessed, retrospectively. Data were available for 202 patients (146 male, 56 female; age 58 +/- 16 years) with a total number of 829 teicoplanin trough plasma levels (C(min)) assessed. The percentage of patients with adequate teicoplanin concentrations (C(min) >/= 10 mg/L) during the treatment period substantially increased from 3.2% on day 2, to 35%, 70%, 90% and approximately 95% on days 4, 7, 11 and 15, respectively. The findings suggest that optimal teicoplanin therapy was achieved only after at least 4, and probably 7, days of therapy in most cases, mainly because of a failure to use an appropriate loading dose. Among the possible causes for the reluctance to use a loading dose, concern over the potential nephrotoxicity of teicoplanin was a major factor. We conclude that loading doses of teicoplanin (6 mg/kg every 12 h for at least three doses) must be considered mandatory in all patients, regardless of their renal function, to enable optimal drug concentrations to be achieved early in the treatment period. Subsequently, TDM is important to ensure that dose regimens are optimized to the individual requirements of the patients.

Adult↗
PubMed2003

Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with lower respiratory tract infections.

Levofloxacin is considered an effective antibiotic in the treatment of community-acquired lower respiratory tract infections (LRTIs). A study was carried out on 17 in-patients to assess the pharmacokinetics of a 500 mg once-daily switch intravenous (i.v.)/oral regimen of levofloxacin in the treatment of LRTI patients. Blood samples were collected under steady-state conditions at appropriate intervals. Levofloxacin plasma concentrations were analysed by means of HPLC and pharmacokinetic parameters were estimated using the WinNonlin pharmacokinetic software package. A lower clearance of levofloxacin (<2 mL/min/kg), conditioning both a longer elimination half-life (approximately 9 h) and a larger AUC(0-tau) (approximately 80 mg/L x h), was observed for both routes in our patients than in healthy volunteers. These differences may be explained considering that levofloxacin is excreted mainly as unchanged drug by the renal route, and most of our patients (71%) were very elderly subjects whose renal function physiologically declines with age. The almost complete (> or =99%) absolute oral bioavailability suggests that a comparable exposure to the iv regimen may be achieved after oral administration. The overall clinical success rate was 94.1%.

Administration, Oral↗
PubMed2003

Levofloxacin disposition in cerebrospinal fluid in patients with external ventriculostomy.

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 (C(max ss))was 10.45 mg/liter in plasma and 4.06 mg/liter in CSF, respectively, with the ratio of the C(max ss) in CSF to the C(max ss) in plasma being 0.47. The areas under the concentration-time curves during the 12-h dosing interval (AUC(0-tau)s) were 47.69 mg. h/liter for plasma and 33.42 mg. h/liter for CSF, with the ratio of the AUC(0-tau) for CSF to the AUC(0-tau) 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.

Adult↗
PubMed2003

Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia.

OBJECTIVE: To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily. DESIGN: Prospective non-blinded pharmacokinetic-pharmacodynamic study. PARTICIPANTS: Ten critically ill adult patients with normal renal function. METHODS: Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed. RESULTS: Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases. CONCLUSIONS: The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.

Aged↗
PubMed2003

Disposition of liposomal daunorubicin during cotreatment with cytarabine in patients with leukaemia.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of liposomal daunorubicin (DaunoXome) 80 or 100 mg/m(2) on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia. DESIGN: Unblinded pharmacokinetic-pharmacodynamic study. PARTICIPANTS: Twenty-three adult patients with acute leukaemia. METHODS: Blood, bone marrow and urine samples were collected at appropriate intervals on days 1-6. Total daunorubicin and daunorubicinol concentrations in plasma, bone marrow, peripheral blood cells and urine were measured by high performance liquid chromatography. RESULTS: Liposomal daunorubicin exhibited a markedly different pharmacokinetic behaviour from the free drug due to a slow distribution of the liposomal moiety into the body. The ratio of area under the concentration-time curve (AUC) for metabolite to parent drug was lower for liposomal daunorubicin than for free daunorubicin, mainly due to higher concentrations of the parent drug in plasma, whereas daunorubicinol exposure was more or less comparable, if not higher. After liposomal daunorubicin at both 80 and 100 mg/m(2), total daunorubicin concentrations in leukaemic cells were at least similar to those observed for free daunorubicin, and significant accumulation was also observed in bone marrow blast cells. Nineteen of 23 patients obtained a complete remission, although 13 had P-glycoprotein-overexpressing blast cells. Grade 3-4 mucositis was found only in three patients with very high AUCs for total daunorubicin and daunorubicinol. CONCLUSIONS: Liposomal daunorubicin at both 80 and 100 mg/m(2) in combination with cytarabine may represent a valid treatment for high-risk acute leukaemia. Liposomal daunorubicin may be helpful in overcoming multidrug resistance, since it shows significant accumulation into tumour target cells, irrespective of P-glycoprotein expression. The tolerability profile suggests that toxicity may be related to exposure to both the parent drug and the metabolite.

Adolescent↗
PubMed2002

TDM coupled with Bayesian forecasting should be considered an invaluable tool for optimizing vancomycin daily exposure in unstable critically ill patients.

A randomized two-arm prospective study was planned to assess the role of therapeutic drug monitoring (TDM) coupled with a Bayesian approach in tailoring vancomycin dosages in unstable critically ill patients. Group A (n=16) had their regimen adjusted day-by-day according to TDM and Bayesian forecasting (D(a)); group B (n=16) had their regimen adjusted day-by-day according to Moellering's nomogram (D(M)). Blood samples were collected every 1-2 days to assess the trough and peak plasma concentrations. In group A, the tailored D(a) required for optimizing vancomycin exposure were considerably higher than the D(M) in 7/16 cases, and lower than the D(M) in 1/16 cases. In group B, standard D(M) caused under-treatment in 3/16 cases and over-treatment in 4/16 cases. Most of these patients concomitantly had some conditions that might have altered vancomycin disposition. The TDM-guided Bayesian-based approach should be considered an invaluable tool for clinicians to handle appropriately on real-time vancomycin therapy in critically ill patients.

Adult↗