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Beta-Lactamase Inhibitors
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Pascalis Vergidis, Matthew E. Falagas
Relebactam (formerly MK-7655) is a non-beta-lactam beta-lactamase inhibitor belonging to the diazabicyclooctanes and features an unusual strained bicyclic urea bearing an aminoxy sulfate (Drawz et al., 2014; Mangion et al., 2011). In combination with imipenem, it has demonstrated potent in vitro activity against Ambler class A and class C beta-lactamases (Hirsch et al., 2012; Lapuebla et al., 2015b; Livermore and Mushtaq, 2013; see Chapter 37, Imipenem–Cilastatin and Imipenem–Relebactam).
Pharmacotherapeutic advances for recurrent urinary tract infections in women
Published in Expert Opinion on Pharmacotherapy, 2020
Mohamad Moussa, Mohamed Abou Chakra, Athanasios Dellis, Yasmin Moussa, Athanasios Papatsoris
Relebactam, is a novel piperidine analog, non-β-lactam bicyclic diazabicyclooctane β-lactamase inhibitor, that is active in vitro against class A β-lactamases, including KPC-type carbapenemases, and class C β-lactamases. Relebactam has been combined with the carbapenem/renal dehydropeptidase I inhibitor imipenem/cilastatin, primarily to restore imipenem’s clinical activity against KPC-producing K.pneumoniae as well as other CRE [144]. In a RCT, phase 3 trial hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or cUTI infection caused by imipenem-non-susceptible pathogens were randomized. I-R is an efficacious and well-tolerated treatment option for carbapenem-non-susceptible infections, where a favorable overall response was observed in 71% I-R and 70% colistin+imipenem patients [145]. A safety profile analyses confirm further evidence that I-R had a more favorable renal safety profile than colistin-based therapy in patients with serious, imipenem-non-susceptible gram-negative bacterial infections [146].
The role of PK/PD–based strategies to preserve new molecules against multi-drug resistant gram-negative strains
Published in Journal of Chemotherapy, 2020
Chiara Adembri, Iacopo Cappellini, Andrea Novelli
Imipenem/Relebactam (IMI/REL) is a combination of the carbapenem imipenem and relebactam, a diazabicyclooctane beta-lactamase inhibitor with a similar structure of avibactam but with an additional piperidine ring.31 Relebactam has been shown to be efficient against serine β-lactamase class A and C and some class D. It has no effect on class B and OXA48 class D. Imipenem (always administered with cilastatin) is a time-dependent antibiotic and a prolonged infusion is necessary in order to obtain at least a target of fT > MIC 69% for bacteriostasis.31 In order to be effective, relebactam needs to have a concentration of 4 mg/L and the PK/PD index predicting efficacy is fAUC/MIC, with a target value of 7.5.32 IMI/REL has recently been approved for the treatment of cUTIs and IAIs. While IMI/REL shows potential restoration of activity in isolates resistant to imipenem/cilastatin, much less data are available on its role in clinical practice, including its stability against the development of resistance. In relebactam, desulfation (and consequent inactivation) occurs more slowly than in avibactam, but relebactam shows a reduced inhibitory potency than avibactam (about 1/8).33 This combination, unlike the other BLI/BLI, is administered as a 30 min infusion. The optimal duration of administration has not yet been validated in the clinical setting.
Developments on antibiotics for multidrug resistant bacterial Gram-negative infections
Published in Expert Review of Anti-infective Therapy, 2019
Georgios L. Voulgaris, Maria L. Voulgari, Matthew E. Falagas
In vitro and in vivo studies determined that relebactam seems to restore the activity of imipenem-cilastatin against imipenem-resistant bacteria. Relebactam has increased the susceptibility over 70% of imipenem-resistant P. aeruginosa, hence reducing the MIC90 from 16 mg/L to 2 mg/L [54,55]. Moreover, the combination of imipenem-cilastatin/relebactam significantly improved the activity against KPC-producing K. pneumoniae, Enterobacter spp. and E. coli [53]. However, no efficacy from the addition of relebactam was observed against A. baumannii [53]. Finally, relebactam does not protect imipenem-cilastatin against class B β-lactamase including IMP, NDM and VIM [56,57]. Similarly to other carbapenems, the time that the imipenem concentration exceeds the MIC of the pathogen (%T> MIC index) has been shown to correlate best with maximum efficacy in experimental infection models [58].