Antibiotic therapy in hematological neutropenic patients: what is the news?

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.

Pharmacology of drugs for hyperuricemia. Mechanisms, kinetics and interactions.

The pharmacological profile of drugs for hyperuricemia is reviewed. These agents may reduce the amount of uric acid in blood by means of two different ways: (1) by reducing uric acid production through the inhibition of the enzyme xanthine oxidase (as allopurinol); (2) by increasing uric acid clearance through an inhibition of its renal tubular reabsorption (as probenecid), or through its metabolic conversion to a more soluble compound (as urate oxidase). Allopurinol is rapidly converted in the body to the active metabolite oxypurinol whose total body exposure may be 20-fold greater than that of the parent compound due to a much longer elimination half-life. Allopurinol undergoes several pharmacokinetic interactions with concomitant administered drugs, some of which may be potentially hazardous (especially with mercaptopurine and azathioprine). Probenecid is an uricosuric agent which undergoes extensive hepatic metabolism and whose elimination after high doses may become dose dependent. It may inhibit renal tubular secretion of several coadministered agents, including methotrexate and sulphonylureas. Rasburicase is a recombinant form of the enzyme urate oxidase which catalyzes the conversion of uric acid to the more soluble compound allantoin. Unlike allopurinol, it does not promote accumulation of hypoxanthine and xanthine in plasma, thus preventing the risk of xanthine nephropathy. Rasburicase showed no significant accumulation in children after administration of either 0.15 or 0.20 mg/kg/daily for 5 days. Rasburicase probably undergoes peptide hydrolysis and in in vitro studies was shown neither to inhibit or induce cytochrome P450 isoenzymes nor to interact with several drugs, so that no relevant interaction is expected during cotreatment in patients.

Antimicrobial agents in elective surgery: prophylaxis or "early therapy"?

A lack of a clear distinction between antimicrobial prophylaxis and therapy still exists in the surgical setting. Major concerns are: 1) Which surgical procedures are eligible for antimicrobial prophylaxis? 2) Which kind of antimicrobial agent should be used for surgical prophylaxis? 3) What is the optimal timing for administering antimicrobial prophylaxis and how long should administration be continued? In this paper we assess the rationales leading to the following answers: 1) Only clean-contaminated and prosthetic clean operations should be eligible for antimicrobial prophylaxis, whereas contaminated or dirty operations should be eligible for "early therapy". 2) First- or second-generation cephalosporins or aminopenicillin/beta-lactamase inhibitors are optimal choices for surgical prophylaxis, depending on location of the surgical wound. 3) The highest licensed dosage of the chosen antimicrobial agent should be administered at induction of anesthesia and redosing should be considered when the intervention lasts more than 2 antibiotic half-lives. This allows maintenance of optimal drug exposure against the potential pathogens in plasma and in the extracellular environment of the potentially contaminated tissues for the entire procedure and for some hours after wound closure. Post-surgical doses are not recommended in most cases whereas ultra-short prophylaxis is preferred.

Protocol implementation in hospital infection control practice: an Italian experience of preoperative antibiotic prophylaxis.

This study evaluates the effectiveness of a protocol implemented to induce behavioural modifications in healthcare workers (HCWs). A preoperative antibiotic prophylaxis protocol for surgical procedures in clean and clean-contaminated wounds was used. The study was conducted in a 300-bed Italian university hospital between 1998 and 1999. The protocol's impact was analysed by retrospective examination of the clinical records for selected common surgical procedures. The study also investigated the reasons for the low compliance with the protocol through a focus group methodology. We examined 723 surgical procedures and the overall compliance was 30.8% (56/182) before the implementation of the protocol and 45.2% (76/168) after 1 year (P< or = 0.01). During the same period compliance with the use of antibiotics increased when antibiotics were recommended by the protocol (5/115 vs. 19/109, P< or = 0.01) and use decreased when they were not (51/67 vs. 57/59, P< or = 0.01). As reported in the focus groups, reasons for low compliance included hospital policy weaknesses in protocol definition and implementation and the cultural behaviour of HCWs. Our results reinforce previous findings that monitoring the effectiveness of protocol implementation in the medical care setting is essential. Critical points that might increase the effectiveness of protocol implementation have also been identified.

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia.

Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t1/2alpha 4.54 +/- 0.87 h; VdSS 2.88 +/- 0.93 l/m2; Cl 0.47 +/- 0.26 l/h/m2) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC0-infinity 456.27 +/- 182.64 microg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200-to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 +/- 7.13 microg/ml x h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorubicin captation in normal tissues. thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy.

High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures.

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.

Liposome-encapsulated daunorubicin for PGP-related multidrug resistance.

The possibility that Daunoxome (DNX), a combination of daunorubicin (DNR) with a liposomal targeting system, escapes PGP was tested. Two pairs of leukaemic cell lines, each consisting of the parental non-multidrug resistance (MDR) line and of a MDR variant, were studied for cytotoxicity (MTT test) and for cellular DNR kinetic and accumulation (flow cytometry). DNX and free DNR were equally toxic against non-MDR cells, whereas the liposomal anthracycline was more toxic than the free drug against the MDR variant. Non-MDR cells accumulated DNR more rapidly when they were exposed to free DNR than to DNX, but MDR cells accumulated more DNR when they were exposed to DNX. The kinetics of DNX and free DNR were also studied in the blast cells of 41 cases of acute leukaemia and they were found to be related to blast cell PGP expression. In 15 cases with a low PGP expression intracellular DNR accumulation was faster and higher with free DNR than with DNX. In 26 cases with a high PGP expression the area under the curve was similar with DNX and free DNR, but the kinetics of intracellular DNR accumulation showed an early low plateau with free DNR and a slow and continuous increase with DNX. In MDR cell lines the ratio was more favourable to DNX than to free DNR. We conclude that liposome encapsulated DNR is partially protected from PGP and that it is worth testing for the treatment of PGP-positive acute leukaemia.

Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia.

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) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); P < 0.01] and IDAOL [2896.60 (736.38) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l x h(-1) x m(-2) vs 139.65 (69.45) l x h(-1) x 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) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) microg x h x l(-1) vs 1028.49 (603.95) microg x h x 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) microg x h x l(-1) vs 2896.60 (736.38) microg x h x 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 x 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.

Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in acute non-lymphocytic leukemia.

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated with a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective downmodulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in several normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigned to receive the same standard chemotherapy regimen of arabinosyl cytosine and idarubicin (IDA) for remission induction or consolidation, without or with CsA. Twenty-eight patients received 36 courses of chemotherapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuous i.v. infusion for 72 h. Whole blood CsA steady-state concentration ranged between 0.61 and 1.14 microM. The IDA area-under-the-curve was about twice as high in the cases that received CsA than in the other cases. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conjugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bacteremia, and with a delayed hemopoietic recovery. In conclusion, this study showed that an attempt at an effective downmodulation of Pgp-mediated MDR would substantially increase the hemopoietic and mucosal toxicity of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA.

Effects of different sampling strategies on predictions of blood cyclosporine concentrations in haematological patients with multidrug resistance by Bayesian and non-linear least squares methods.

The Bayesian method (BM) can use previous information for the optimization of dosage regimen. However, Bayes' law remains true when the parameters are obtained from the infinite population. Therefore a bias might exist in the previous information and affect BM predictive performance. To overcome this shortcoming, the blood drug concentration of a patient can be used to individualize his pharmacokinetic parameters. Until now, at least two sampling strategies, i.e. steady-state and non-steady-state sampling strategies, have been developed to individualize and predict blood drug concentration. In the present study we used five sampling strategies: (1) all samples; (2) post-infusion samples; (3) during-infusion samples; (4) samples within 95% confidence interval/interquartile range of a steady-state concentration; (5) the sample of the mean/median at the mid-time-point of a steady-state to individualize and predict blood cyclosporine concentrations in haematological patients with multidrug resistance. We investigated the effects of different sampling strategies on BM and the nonlinear least squared method (NLLSM) predictive performances. The results showed that BM predictive performance was better than NLLSM. But the results did not prove that the steady-state sampling strategies were superior to the non-steady-state ones.

Increased spontaneous cell detachment of F10 cells induced in vitro by some calcium-channel blockers.

We investigated the action of some Ca(++)-channel blockers such as flunarizine, nifedipine and verapamil on F10 cells in vitro. Cell adhesion to the growth substratum, evaluated by the technique of spontaneous detachment in culture medium, is reduced in Ca(++)-channel blocker treated cells by comparison with controls. In our opinion such an event could also explain the inhibitory effect on cell growth and colony forming ability.

The effect of Dilazep on F10 cells in vitro.

Experiments on F10 cell growth, colony ability, cell adhesion and ultramorphology at SEM have been performed. The effect of Dilazep (DIL) has been compared with that of well known modulating agents such as Flunarizine (FLU) and Verapamil (VER) on cells cultured in high Ca++ medium (HCM) and in low calcium medium (LCM). While in HCM there is no difference among the three drugs, FLU and VER had a stronger effect on cell growth inhibition in LCM. Cell adhesion to the growth substratum, evaluated by the technique of spontaneous detachment in culture medium, is reduced in DIL treated cells in comparison to the controls.