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This article provides a comprehensive review of currently available treatment options for infections due to carbapenem-resistant Enterobacteriaceae CRE. Antimicrobial resistance meropenemm Gram-negative bacteria is an emerging and serious global public health threat. Despite this increasing burden, the most optimal treatment for CRE infections is largely unknown. For the few remaining available treatment options, there are limited efficacy data to support their role in therapy.
Optimization of dosing regimens and combination therapy are additional treatment strategies being explored. Carbapenem-resistant Enterobacteriaceae infections are associated with poor outcomes and high mortality. Continued research is critically needed to determine the most appropriate treatment. Antimicrobial resistance is globally recognized as one of the msropenem threats to public health. Of particular concern are infections caused by resistant Gram-negative bacilli, which are increasingly being reported worldwide.
The prevalence of CRE infections has increased over the last decade, especially in healthcare settings, and as antiibotik CRE have been recognized by the US Centers for Disease Control and Prevention as an urgent public health threat [ 23 ]. The Centers for Disease Control and Prevention estimates that more than healthcare-associated infections are caused by the 2 most common type of CRE, carbapenem-resistant Klebsiella species and Escherichia species, each year in the United States [ 3 antbiiotik.
Carbapenem-resistant Enterobacteriaceae can cause a number of serious infection types such as intra-abdominal infections, pneumonia, urinary tract infections, and device-associated infections or asymptomatic colonization [ 4 — 6 ]. Each year approximately deaths result from CRE infections [ 3 ]. This result may be due to delayed time to active therapy, pharmacologic limitations of available treatment options, and the fact that patients with CRE infections tend to be critically ill.
At this time, there are a limited selection of treatment options for CRE infections. Additional CRE treatment strategies include optimization of dosing regimens and combination therapy.
This review will focus on the current treatment options for CRE infections. There are numerous different types of carbapenemase enzymes, each conferring varying spectrums of resistance. In vitro activity of carbapenems in the setting of one of these enzymes is variable, and the exact role of carbapenems in infectious due to these organisms is controversial.
To further complicate treatment, CRE often exhibit resistance to structurally unrelated antimicrobial classes such as aminoglycosides and fluoroquinolones [ 11 ]. However, aminoglycoside susceptibility can vary as a function of K pneumoniae carbapenemase KPC strain type and coexisting aminoglycoside modifying enzymes, which are not tested in a traditional clinical laboratory.
The emergence of resistance during therapy is another emerging concern [ 1213 ]. Despite their increasing burden, the most optimal treatment for CRE infections is largely unknown. At this time, there are no published data from randomized controlled trials assessing antimicrobial treatment options for CRE infections.
Although this information is important, in the United States at this time there may not be a sufficient number of patients with serious CRE infections to conduct such a trial. Therefore, much of the existing evidence is from reviews of case reports, case series, and small retrospective studies, which have a number of inherent limitations [ 1415 ].
For patients who are critically ill or with deep-seated infections, consider empiric and antibiogram-directed combination therapy with 3 drugs. There are limited clinical data supporting the use of aminoglycosides, rifampin, and fosfomycin. If any of these drugs have in vitro activity and are selected for use especially for infections outside the urinary tract for aminoglycosides and fosfomycinconsider use in combination with 2 other in vitro active drugs due the potential for the emergence of on-treatment resistance.
If tigecycline is used as an adjunct drug, consider the tigecycline MIC and risks and benefits of using high dosing vs traditional dosing. Intravenous fosfomycin is not available in the United States.
However, combination therapy may still be warranted due to the potential for the emergence of resistance. In critically ill patients, strongly consider combination therapy.
It is important to weight the risks and benefits of alternative dosing, which may be necessary to treat serious CRE infections. In this study, even at an MIC of 4. In Europe, IV formulations are available. Outside the United States, IV fosfomycin has been used for a wide range of infections including bacteremia, osteomyelitis, and meningitis at daily doses of 1—16 g divided in 3 or 4 doses. For the treatment of isolates with higher MICs, higher doses of up to 20 g per day, administered by prolonged or continuous infusion, may be considered.
However, there are little data on the safety of higher-dose regimens [ 348283 ]. Although pharmacokinetic data appears favorable, there ,eropenem only limited clinical data assessing the efficacy of carbapenem monotherapy in the treatment of CRE infections.
In antibiktik study that compiled data from meroopenem studies, in 44 patients treated with carbapenem monotherapy for infections due to carbapenemase-producing K pneumoniaetreatment efficacy varied based on MIC [ 20 ]. In a recent review, the mortality rate associated with carbapenem monotherapy was unacceptably high In addition, several retrospective studies have observed lower rates of mortality with carbapenem-based combination therapy compared with noncarbapenem combination therapy [ 20 — 23 ].
The efficacy of carbapenem combination therapy also appears to be MIC dependent. In a review of 20 clinical studies, carbapenem-containing regimens were associated with lower mortality than noncarbapenem-containing regimens Although meropenrm findings are encouraging, it is important to note that antbiiotik all reports have focused on carbapenem-containing regimens.
Actual mortality rate for drug of interest not included in referenced study. For more information see referenced study. Dual-carbapenem combination treatment may be an effective option for infections caused by pandrug-resistant CRE; however, data are limited mrropenem selected case reports [ 2526 ].
Meronem IV mg & 1g – Summary of Product Characteristics (SmPC) – (eMC)
Experimental data have shown that the KPC enzyme may have increased affinity for ertapenem than other carbapenems; therefore, when given together, KPC preferentially deactivates ertapenem, which hinders degradation and improves the activity of the concomitant carbapenem [ 2728 ]. In case reports, ertapenem plus either doripenem or meropenem has been used successfully to treat select pandrug-resistant and colistin-resistant KPC-producing K pneumoniae infections bacteremia, VAP, and UTI.
Dual-carbapenem combination treatment is a promising option, which may be most effective in combination with a third drug [ 29 ]. Colistin polymyxin E and polymyxin B are considered to be the most active in vitro agents against CRE [ 30 ].
Polymyxin B and colistin differ by a single amino acid. There are several potential advantages to the use of polymyxin B over colistin, many of which stem from the fact that colistin is administered as the inactive prodrug colistimethate CMS. Because the conversion of CMS to colistin is slow and inefficient in patients with normal renal function, the majority of CMS is cleared before conversion to colistin. Therefore, despite being dosed at a lower milligram per kilogram per day dose, polymyxin B can zntibiotik higher peak serum concentrations, which are achieved much more rapidly than with colistin [ 3132 ].
Loading and maintenance doses and dosing mdropenem in table based on the largest pharmacokinetic studies to date, which developed the first scientifically based dosing suggestions for colistin meropenej polymyxin B [ 3132 ].
However, note this target should be based on MIC, site, and severity of infection. Colistin may be best used as a part of combination therapy for patients with good renal function. Renal dose adjustments are necessary for colistin and CMS but are not required polymyxin B [ 29 ].
The reason for this is that there is minimal renal clearance of colistin, but the prodrug CMS is predominately cleared renally antibiotiik 29 ]. As with colistin, polymyxin B undergoes extensive renal tubular reabsorption and is eliminated by mostly nonrenal clearance.
More importantly, however, polymyxin B package insert dosing recommendations include vague renal dosing adjustments that have been followed in all of the polymyxin B literature to date. The efficacy and safety of nonrenally adjusted polymyxin B remains unclear. The renal clearance of CMS meropeem an advantage over polymyxin B that a higher concentration of active drug in the urine is reached, which would make colistin and CMS a viable UTI treatment alternative [ 2933 ].
Despite the potential advantages of polymyxin B zntibiotik, the majority of clinical data to date for CRE infections has focused on the use of colistin. The ideal dosages of colistin and polymyxin B are largely unknown, especially in the case of renal failure, renal replacement therapy, and critical illness [ 34 ]. For serious infections caused by resistant Gram-negative pathogens, high total daily doses of colistin appear to be important to maximize treatment efficacy [ 3135 ].
In a retrospective study of patients treated with CMS, In a retrospective study of 76 patients with Gram-negative bacteremia, the median colistin dose was higher in patients who achieved microbiological success 2.
Meropenem – Wikipedia
Another retrospective study found similar results with polymyxin B treatment [ 37 ]. Historically, neurotoxicity was an important concern with the use of polymyxins; however, with current formulations, this side effect is reported less frequently.
Patients discussed in the recent literature are more critically ill, ventilated, and sedated, which might significantly limit the ability to detect neurotoxicity, which is primarily manifested as paresthesias and ataxia. The use of colistin and polymyxin B at higher doses, which may be necessary for CRE infections, may be associated with a higher risk of nephrotoxicity [ 3537 ].
The better outcomes associated with high-dose colistin may come at the cost of worsening renal function [ 35 ].
Another concern with the use of polymyxins is on-treatment resistance development. Blood isolates from 1 patient infected with carbapenem-resistant K pneumoniae and treated with polymyxin B monotherapy showed a significantly increased polymyxin B MIC in just 5 days 0. In addition, there have been reports of colistin-resistant, carbapenem-resistant K pneumoniae outbreaks [ 4142 ].
Therefore, polymyxins may be most effective as part of a combination for serious CRE infections [ 3443 ]. In a recent review that used compiled data on patients with CRE infections bacteremia, pneumonia, intra-abdominal infections, UTIs, and surgical site infectionsthe mortality rate for colistin monotherapy was A review of 15 studies which included 55 unique patients found that clinical success was lower for colistin monotherapy compared with colistin combination therapy for treatment of infections caused by KPC producers The majority of CRE isolates remain active against tigecycline in vitro; however, resistance to tigecycline is increasing [ 46 — 48 ].
There are only limited clinical data to support use of tigecycline monotherapy for infections caused by CRE that demonstrate in vitro susceptibility [ 2223444950 ]. A review which included a small number of patients with carbapenem-resistant K pneumoniaefound that In addition, despite in vitro susceptibility, on-treatment resistance emergence has been described [ 1343 ].
However, high-dose tigecycline may only transiently lead to increased plasma concentrations, because higher doses may lead to increased intracellular accumulation and tissue distribution [ 51 ].
In 30 complex patients with severe intra-abdominal infections due to KPC-producing K pneumoniaehigh-dose tigecycline in combination with colistin was associated with lower mortality compared with approved dose tigecycline plus colistin [ 53 ].
In a review that used compiled data on patients with various types of CRE infections, the mortality rate with tigecycline monotherapy was In Europe, an intravenous fosfomycin formulation is available. The use of intravenous fosfomycin monotherapy for the treatment of systemic infections may be limited due to the potential for the development of drug resistance during treatment [ 62 ]. Gentamicin is generally the most active aminoglycoside in vitro against carbapenem-resistant K pneumoniae ; however, amikacin can be most active against other CRE [ 496364 ].
Data on the use of aminoglycosides as monotherapy are limited, and aminoglycosides monotherapy appears to be most efficacious in the treatment of UTIs [ 154465 ]. In a retrospective cohort study of cases of carbapenem-resistant K pneumoniae bacteriuria, treatment with an in vitro active aminoglycoside was associated with a significantly higher rate of microbiologic clearance compared with either polymyxin B or tigecycline [ 65 ].
In multivariate analysis, aminoglycoside treatment was independently associated with microbiologic clearance. Aminoglycoside therapy may be most appropriate as a component of combination therapy for infections, especially UTIs, caused by CRE [ 66 — 68 ].
In the largest CRE bacteremia cohort study to date, the mortality rate for aminoglycoside monotherapy was In a review which included 24 cases of aminoglycoside combination therapy most often with colistin, carbapenems, fluoroquinolones, and tigecyclineall patients who failed aminoglycoside-based combination therapy had bloodstream infections [ 68 ].
In a review of 20 clinical studies, the combination of an aminoglycoside and a carbapenem had the lowest mortality rate