- 極めて重要な抗菌薬であるceftazidime / avibactamとmeropenem / vaborbactamを今後も注視する必要あり。
- ceftazidime / avibactamとmeropenem / vaborbactamは、CRE感染の治療に革命的
- OXA-48 like に対して、Ceftazidime/avibactam良いかも
- MBLに対して、ceftazidime / avibactam + aztreonamは選択を考慮できる。
- 各施設のKPC vs. OXA-48 vs. MBL出現状況から、選択する。
Ceftazidime/avibactam and Meropenem/vaborbactam are changingthe management of invasive infections due to carbapenem-resistant enterobacteriaceae (CRE) leading to higher rates of clinical cure, decreased mortality, and decreased rates of acute kidney injury when compared to colistin-based regimens. However, these two agents are not interchangeable with regards to management of CRE infections, and clinicians need to be aware of their differences. This review focuses on differences in in vitro activity of these agents as a function of mechanism of carbapenem resistance, the clinical data supporting their superiority over colistin-based therapy, and the differences between agents with regards to propensity for selection of resistance. Furthermore, considerations and recommendations for hospital formularies and antibiotic stewardship programs regarding positioning of these agents are discussed.
Considerations for formulary decisions:
Both ceftazidime/avibactam and meropenem/vaborbactam have revolutionized themanagement of CRE infections and clinicians are fortunate to have these “game-changing” therapies. For the management of infections due to KPC-producers, treatment with these agents is associated with
decreased mortality, improved clinical success, and decreased toxicity compared to older options such as colistin.
Ceftazidime/avibactam was the first new antibiotic to come to market for CRE. Real world data have emerged demonstrating its superiority to polymyxin-based therapy from both efficacy and safety standpoints [16, 17]. While it remains unclear whether this agent should be administered as monotherapy or combined with other agents (e.g. aminoglycosides), ceftazidime/avibactam represents an effective treatment option for KPC-producers. However, issues pertaining to the emergence of resistance during therapy are concerning. The similarities in emergence of resistance in pre-clinical [21, 22] and clinical studies [23, 26-27] are striking.
The enhanced in vitro potency of meropenem/vaborbactam (MIC50/90 of 0.06/1 compared to 1/4) against KPC-producers as well as data suggesting that emergence of resistance is less likely to occur, make meropenem/vaborbactam, in our opinion, the preferred agent for treatment of KPC-producing CRE. Importantly, it will be crucial to assess whether these advantages translate to improved outcomes.
Furthermore, as resistance to meropenem/vaborbactam develops in clinical isolates, the mechanisms of resistance as well as activity of ceftazidime/avibactam against these meropenem/vaborbactam-resistant isolates will further inform considerations regarding a preferred agent. If one agent were less likely to select for resistance mechanisms that cause resistance to both novel therapies (and other pipeline agents) it would be an important consideration when deciding on a preferred agent. Encouragingly, data suggest cross-resistance currently remains infrequent . Of 991 KPC isolates tested only 24 (2%) displayed resistance to either agent. Importantly only 5 (21%) were resistant to both, with 14/18 (78%) of ceftazidime/avibactam-resistant isolates being susceptible to meropenem/vaborbactam and 6/10 (60%) meropenem/vaborbactam-resistant isolates remaining susceptible to ceftazidime/avibactam .
Clinicians will need to pay attention to emerging resistance trends and local susceptibility data to continually assess which agent maintains better activity and is less likely to select for cross-resistance.
Due to avibactam’s unique inhibitory profile against OXA-48 like enzymes and ceftazidime’sstability to hydrolysis by this enzyme, ceftazidime/avibactam is the preferred agent for treatment of OXA-48-producing CRE. Furthermore, avibactam’s broad inhibitory profile also makes it an ideal agent tocombine with aztreonam for the management of MBLs. MBLs do not have the ability to hydrolyze aztreonam. However, due to frequent co-production of other enzymes (e.g. ESBLs, OXA-48) MBL- producing enterobacteriaceae are often resistant to aztreonam. Concomitant administration of avibactam, which can inhibit all non-MBL enzymes present, can restore aztreonam’s activity. This has been demonstrated in vitro where addition of 4 mg/L of avibactam decreased the MIC of aztreonam to ≤0.5 mg/L in seven aztreonam-resistant MBL producers . Although the aztreonam/avibactam combination antibiotic is currently under development and is unavailable, combining ceftazidime/avibactam with aztreonam is an emerging treatment strategy for MBL-producers that has been employed with varying degrees of clinical success [32, 33].
In conclusion, clinicians will likely have a need for both agents for the management of CRE. Ultimately, local CRE epidemiology will drive decisions regarding the preferred agent, based on the most frequent mechanism of carbapenem resistance (KPC vs. OXA-48 vs. MBL) within an institution. Furthermore, because resistance mechanisms are complex and often multifactorial, we recommend that all CRE pathogens be routinely tested against both ceftazidime/avibactam and meropenem/vaborbactam. While one agent might be preferred for empiric use based on local epidemiology, individualized definitive therapeutic decisions should be based upon characteristics of the patient and pathogen being treated. Moreover, as reports of resistance development while on therapy
have emerged, it is critical that repeat susceptibility testing is performed in patients with persistently positive cultures that to ensure that resistance has not developed to the agent utilized.
+++ = activity >90%, would expect in vitro activity; ++ = activity 60-90%, high likelihood of in vitro activity, but ensure susceptibility prior to using; + = activity 30-60%, lower likelihood of susceptibility; - minimal to no activity, should not be considered an option; * might have activity, but driven by meropenem, vaborbactam does not add anything in this setting.
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