• Senior investigator: P.M. Tulkens
• Non-doctoral fellow (junior investigator): E. Viaene (2000-2002), V. Basma (2003-2004)
  

Supported by the

• Ligue Belge de Lutte Contre la Mucoviscidose / Belgische Vereniging voor Strijd tegen Mucoviscidose
• Fondation Roi Baudouin / Koning Boudewijn Stichting

• Administration of aminoglycosides in a "once-a-day" schedule
• Evaluation of phospholipiduria and apoptosis as a means to monitor aminoglycoside-induced renal alterations
• Evaluation of ß-lactam antibiotics in special applications

This new model of administration was proposed on the basis of experimental studies demonstrating its potential for being more, or at least as effective than the conventional schedules (3 times a day), while causing less toxic reactions. The lower toxicity stems from the saturable character of aminoglycoside uptake by target tissues (kidney, inner ear). Moreover, the toxicity induced by aminoglycosides proceeds by successive thresholds from recoverable alterations towards irreversible damage. Keeping the level of alterations below a critical threshold results therefore in an effective protection of the patient. The 'once-a-day' schedule new scheme was successfully tested in several patient populations and is now introduced in a large number of applications of these drugs (suitable modifications of the official package inserts have been made in several countries including Belgium for two aminoglycosides so far).
 

Evaluation of phospholipiduria and apoptosis as a means to monitor aminoglycoside-induced renal alterations

We developed this approach in parallel to the above studies on aminoglycosides, because it provides a direct way to monitor non invasively the early alterations which aminoglycosides cause in kidney cortex. A series of patient populations have been examined so far, ranging from premature children, neonates, young females, patients suffering from cancer with or without granulocytopenia, to intensive care patients and HIV positive patients. Drugs examined so far have included netilmicin and amikacin. A trial with tobramycin is ongoing. Results show that phospholipiduria is a useful marker of impending toxicity in correlation with the duration and extent of treatment. It is also a useful monitoring criteria for assessing the safety of new schedules. It can also be used experimentally to assess the effectiveness of nephroprotectants. The same approach has been used to assess the safety of azithromycin in patients, in connection with the potential of this drug to cause phospholipidosis (see above).
 

Phospholipiduria as an early indicator of aminoglycoside-induced nephrotoxicity. The figure compares the level of urinary phospholipids in cancer patients receiving 6 mg/kg netilmicin daily  as a single injection (qd) or divided in 3 injections over each 24 h period (tid) during 7 days.  Phospholipiduria rises steadily during the treatment period, but returns to normal values within 5 days of treatment discontinuation. Despite the fact that the interindividual variations are important, it clearly appears that the tid administration causes a more rapid and elevated phospholipidurva than the qd administration. The rise caused by tid treatment shows also a slower reversibility (From Van der Auwera et al, 1991, Antimicrob. Agents Chemother.)

In parallel, experimental and clinical studies have been initiated to develop the use of apoptosis markers for the study of aminoglycoside-induced toxicity.
 

Evaluation of ß-lactam antibiotics in special applications in relation with their pharmacodynamic properties

In contrast with aminoglycosides, ß-lactam antibiotics must be administered several times a day, because their serum concentration must ideally remain above the MIC of the offending organisms for the whole period of treatment. While this can be easily achieved in simple applications of these drugs, little is known concerning this aspect in special situations where pharmacokinetic parameters can vary largely from what is observed in 'normal' patients. In this context, we have explored the validity of the registered scheme of administration of aztreonam (a ß-lactam antibiotic with specific activity against Gram (-) bacteria) in two populations at high risk of infection, namely, patients undergoing liver transplantation and patients suffering from cystic fibrosis. We could demonstrate that the officially registered schedules and dosages were markedly inadequate for cystic fibrosis patients. We are currently designing clinical trial aimed at testing rationally designed new schemes, based on the specific pharmacokinetics of aztreonam in this patient population and the pharmacodynamic criteria explained above.  Specifically, we are attempting to develop the administration of azrtreonam by continuous infusion for home therapy with portable, elastomeric pumps.  Pilot studies have established that aztreonam is tsable enough to be administered that way and preliminary studies in non-infected cystic fibrosis patients have demonstrated that a stable serum concentration of up to 32 µg/ml can be obtained without difficulty.

Collaborations