- イミペネムは、 髄膜炎に使用すべきでない。
- Meropenem-vaborbactam は、対 KPC産生Enterobaceriaceae
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Carbapenems are generally resistant to cleavage by most plasmid and chromosomal beta-lactamases and have a very broad spectrum of activity encompassing:
●Gram-negative organisms (including beta-lactamase producing H. influenzae and N. gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa), including those that produce extended-spectrum beta-lactamases
●Anaerobes (including B. fragilis)
●Gram-positive organisms (including Enterococcus faecalis and Listeria)
Carbapenems are not generally active against Stenotrophomonas maltophilia (which has a carbapenem-hydrolyzing chromosomal beta-lactamase), Burkholderia cepacia, Enterococcus faecium, oxacillin-resistant staphylococci, or JK diphtheroids.
Although initial isolates of P. aeruginosa are usually susceptible to the carbapenems, resistance may emerge on therapy when these drugs are used as a single agent. Evidence suggests that carbapenems do not traverse the outer membrane of P. aeruginosa through the normal porin channel used by the other beta-lactams but rather through a different channel. Carbapenem-resistant strains of P. aeruginosa arising on therapy generally have altered permeability to these drugs and specific changes in their outer membrane proteins; such strains are generally not cross-resistant to other beta-lactams nor do they produce increased or novel beta-lactamase activity.
Carbapenem-hydrolyzing beta-lactamases have been increasingly isolated from gram-negative organisms and may limit therapy with these agents in these circumstances.
All carbapenems should be dose-reduced in the setting of renal dysfunction.
Imipenem is inactivated in the proximal renal tubule by the normal human enzyme renal dehydropeptidase I, with resultant low urinary levels of active drug and necrosis of the proximal tubule in the rabbit model. Such cleavage of imipenem is prevented by co-administration of cilastatin, a specific inhibitor of this dehydropeptidase. Imipenem-cilastatin (500 mg IV Q6h with normal renal function) is available for clinical use. The dosing of imipenem should be carefully titrated; patients with glomerular filtration rates of <5 mL/min should generally not receive imipenem unless hemodialysis is ongoing or will start within 48 hours.
Imipenem-cilastatin therapy has been associated with central nervous system (CNS) toxicity, including change in mental state, myoclonus, and seizures. In a meta-analysis of over 100 studies that compared imipenem to a non-carbapenem antibiotic, imipenem use was associated with an excess of 4 seizures per 1000 patients treated. CNS toxicity with imipenem is especially evident in patients with underlying CNS disease or impaired renal function. Imipenem should not be used for the therapy of meningitis.
Meropenem has a spectrum of activity similar to imipenem. Unlike imipenem, meropenem is stable to human renal dehydropeptidase I, so can be administered without cilastatin. Meropenem may have a slightly lower risk of producing seizures than imipenem-cilastatin, but that decrease has not been proven in direct head-to head comparisons of small sample size. Meropenem is useful for the treatment of bacterial meningitis (in pediatric patients >3 months old) and intra-abdominal infection.
Ertapenem is a newer carbapenem with a narrower spectrum of activity than imipenem or meropenem. It is active against most Enterobacteriaceae and anaerobes but less active than the other carbapenems for P. aeruginosa, Acinetobacter, and Gram positive bacteria, particularly enterococci and penicillin-resistant pneumococci. The major benefit of ertapenem over other carbapenems is that it has a long half-life and can be administered once daily. Unlike meropenem, there are insufficient data to support the use of ertapenem for the therapy of meningitis.
Doripenem has demonstrated clinical efficacy in the treatment of complicated urinary tract and intra-abdominal infections. It has a similar spectrum of activity as meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than meropenem.
In 2014, the US Food and Drug Administration (FDA) approved revisions to the doripenem label warning clinicians about increased mortality rates in patients with ventilator-associated bacterial pneumonia who received doripenem rather than imipenem, based on results of a randomized trial that was stopped early due to safety concerns. In the trial, 28-day all-cause mortality was higher and clinical response rates were lower with doripenem compared with imipenem, although different dosing regimens and use of adjunctive aminoglycosides may have influenced these results.
establish the efficacy and safety of doripenem in the setting of bacteremia and other severe infections.
Vaborbactam is a novel broad-spectrum beta-lactamase inhibitor that potently inhibits class A carbapenemases (including K. pneumoniae carbapenemases [KPC]). It is not active against class B or D carbapenemases (ie, metallo-beta-lactamases and OXA-type enzymes). The addition of vaborbactam to meropenem reduces the MICs to meropenem among class A carbapenemase-producing Enterobacteriaceae to wild-type MIC levels. Meropenem-vaborbactam was comparable to piperacillin-tazobactam in a trial of patients with complicated urinary tract infection, and it is being evaluated in patients with bacteremia, hospital-acquired pneumonia, and complicated intraabdominal infections. The main role of this agent is for treatment of KPC-producing Enterobaceriaceae. Clinical data are thus far limited; an as yet unpublished randomized trial comparing meropenem-vaborbactam with the best available therapy for treatment of carbapenem-resistant Enterobacteriaceae infections was stopped early because of better outcomes in the meropenem-vaborbactam arm.
Vaborbactam does not enhance the clinical activity of meropenem against carbapenem-resistant P. aeruginosa or Acinetobacter spp.