A novel strategy of infusion of ceftazidime-avibactam plus aztreonam for the treatment of infections due to OXA48 & NDM producing carbapenem resistantKlebsiella pneumoniae: Time is of the essence

Abstract

Purpose: Ceftazidime-avibactam (CAZ-AVI) along with aztreonam (ATM) is widely used off-label in clinical practice in India for OXA48 plus NDM producing carbapenem resistant Klebsiella pneumoniae (CR Kp). If the level of AVI is maintained at 2.5 mg/ml, it protects ATM from OXA48 and allows it to act against NDM producing CR Kp, for which the MIC to ATM has been found in a published report to be 2 mg/ml. Extrapolative considerations suggest that if CAZ-AVI is infused over 3 hours & ATM over the 2nd half, half an hour after starting the CAZ-AVI infusion, it may be possible to maintain levels of AVI above 2.5 mg/ml & ATM levels above 4 times the assumed MIC of 2 mg/ml, for more than 50% of the dosing interval. This may be a worthwhile strategy for both good efficacy & resistance suppression. Methods: Plasma samples for levels of CAZ, AVI & ATM were collected at 1, 3, 5 h after infusing the drugs in the above-mentioned manner. Drug levels were measured at the Laboratori de Referència de Catalunya in Barcelona, Spain. Results: In this pharmacokinetic proof-of-concept study in 5 consecutive adult patients infected with CR Kp, all levels of ATM at 5 h after beginning the infusion were at or above 20 mg/ml. Conclusion: T > 4xMIC for 50% of the dosing interval was easily achieved in all the patients. This PK/PD index is higher than that needed for optimal killing & is considered as the PK/PD index for resistance suppression.