Carbapenem-resistant Enterobacteriaceae infections make treatment more difficult. What are the advantages of combination therapy?

*For medical professionals' reference only, the rational combined use of antibiotics is an important treatment for clinically refractory infections
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In recent years, with the increase in the use of broad-spectrum antibiotics, multi-drug resistant pathogens, especially those resistant to carbapenem antibiotics, have gradually increased, posing a huge threat to clinical treatment and prevention and control
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In this issue, the author reviews the relevant literature and mainly elaborates the current combined treatment plan of Carbapenem-resistant Enterobacteriaceae (CRE), in order to provide ideas and ideas for the treatment of pan-resistant or even fully resistant Enterobacteriaceae.
Supported by evidence
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1.
Definition and Trend of CRE CRE refers to Enterobacteriaceae bacteria that are resistant to any carbapenem antibiotics of imipenem, meropenem, ertapenem or doripenem
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China’s 2020 CHINET surveillance network shows that Escherichia coli still ranks first in the detection rate and is more sensitive to carbapenem antibiotics; Klebsiella pneumoniae has jumped to the second place in gram-negative bacteria.
The resistance rate to carbapenem antibiotics is close to one-third, showing a high trend
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2.
The main resistance mechanism of CRE The resistance mechanism of Enterobacteriaceae to carbapenem antibacterials is mainly carbapenemase production
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Based on the Ambler classification, it mainly includes the following three categories: KPC is the most common type of enzyme, which can usually hydrolyze almost all β-lactams and aztreonam, and is more common in Klebsiella pneumoniae and Escherichia coli.
Mediates rapid spread; the main epidemic clone of Klebsiella pneumoniae in China is ST11, and most ST11 carries blaKPC-2
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Type B enzymes are mainly metalloenzymes, including NDM, IMP, VIM, SIM, GIM; CRE in China mainly carries the first three metalloenzymes
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Type D enzymes are mainly of OXA type, including OXA-48, OXA-23, OXA-51; they are mainly found in Klebsiella pneumoniae, but Klebsiella pneumoniae carries less OXA-48, mostly in Europe and the United States ST147 type, etc.
; while OXA-23 and OXA-51 are mostly concentrated in the non-fermenting bacterium Acinetobacter baumannii
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3.
The main strategies to deal with CRE infections The current main strategies to deal with CRE infections are divided into two categories: one is the application and research and development of new antibacterial drugs, such as imipenem/cilastatin/raibatane, meropenem / boron by Batan (meropenem-vaborbactam), cephalosporins Loza / tazobactam, ceftazidime / Avi Batan and so on
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Ceftazidime/avibactam, which has been approved for marketing, has brought hope for CRE treatment, but it is ineffective in the treatment of metalloenzyme-producing enterobacteriaceae, and more and more KPC subtypes are also in vivo/in vitro In the research, drug resistance has been induced, which greatly limits its wide clinical application
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A retrospective multicenter study involving 577 patients with infections showed that ceftazidime/avibactam was used to treat 30 cases of lower respiratory tract infections caused by Carbapenem-resistant Klebsiella Pneumoniae (Carbapenem-resistant Klebsiella Pneumoniae, CRKP).
The daily mortality/resistance risk is relatively high
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Although a variety of antibiotics such as cefadil, ceftaroza/tazobactam have achieved good therapeutic effects in phase II or III, they still need to refer to the in vitro susceptibility results of large-scale epidemiology and the results of in vivo experiments.
Come to a conclusion
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The second category is mainly combined anti-infective treatment programs, which mainly include carbapenem-based combined treatment programs; polymyxin-based combined treatment programs; tigecycline-based combined treatment programs; Combination therapy based on aminoglycosides, etc.

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However, when choosing a combined anti-infective treatment plan, it is necessary to consider the patient's infection type (for example, tigecycline should not be applied to bloodstream infections and urinary tract infections; meropenem is more suitable for skin and soft tissue and central nervous system infections; aminoglycosides) Antibiotics are mainly used for the treatment of urinary tract infections), critically ill status (multiple scoring criteria can be used to refine and stratify, early application of combined treatment anti-infective programs), resistance mechanisms (based on local etiological and epidemiological characteristics, combined with The possible resistance mechanisms of CRE; such as the combination regimen based on meropenem is still one of the first options for the treatment of metalloenzyme-producing CRE) and drug sensitivity results, etc.
, in order to accurately and efficiently apply the combined anti-infective treatment regimen to maximize the prognosis
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Based on a number of previous studies, CRE-induced bloodstream infections, hospital-acquired pneumonia, abdominal infections, skin and soft tissue infections, and urinary tract infections can all be combined treatment options
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A systematic review of 15 studies included 55 infected patients (7 received polymyxin monotherapy, 11 received polymyxin combination therapy; 15 received carbapenem monotherapy, 4 patients Receive carbapenem combination therapy), where the infection sites are mainly concentrated in bloodstream infections, lower respiratory tract infections and urinary tract infections.
The main resistance mechanism may be the KPC enzyme-producing Enterobacteriaceae.
After comprehensive analysis, it was found that polymyxin or The clinical success rate of carbapenem monotherapy is low, while the combined anti-infective therapy has a better effect
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Similarly, a systematic analysis of 38 studies included 47% of case-control studies, 35% of retrospective studies, and 17% of case reports, with a total of 105 patients, including single-agent anti-infective therapy and combination anti- The per capita ratio of infection treatment programs is close to 1:1.
The types of infections are mainly bloodstream infections and lower respiratory tract infections.
The study found that compared with combination therapy, single-agent treatment programs have a higher failure rate
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In addition, some scholars included 12 studies with a total of 416 cases (206 cases of single-agent treatment and 210 cases of combined treatment).
The main types of infections were bloodstream infections, lower respiratory tract infections, skin and soft tissue infections, urinary tract infections, and abdominal cavity infections.
Compared with combination therapy, drug anti-infective treatment has a higher mortality rate
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Therefore, for the treatment of bloodstream infections, lower respiratory tract infections, and urinary tract infections caused by CRE, priority should be given to combined anti-infective treatment options
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 However, for CRE-infected patients with a high risk of death, it may be more suitable for early use of combined anti-infective therapy
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In an observational study conducted by two hospitals in Greece (a high-endemic area of ​​CRE) from 2009 to 2010, a total of 205 cases of infections caused by CRKP were included.
The results showed that combined anti-infective treatment programs significantly reduced the mortality of CRKP patients
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Similarly, the well-known retrospective cohort study (INCREMENT study) conducted from January 2004 to December 2013 also confirmed that the combined anti-infective treatment regimen can significantly reduce the risk of death in patients with carbapenemase-producing Enterobacteriaceae infection
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More importantly, a large domestic multi-center retrospective study led by Chinese scholars included 164 cases of blood infection caused by CRE infection in 36 tertiary hospitals in 19 provinces in China from 2013 to 2017.
The results showed that: In patients with metalloenzyme type CRE infection, combined anti-infective treatment may reduce the patient's risk of death
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In other words, patients may benefit more from combined anti-infective therapy than ceftazidime/avibactam therapy
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In addition, it should be noted that for patients with CRE infection with a minimum inhibitory concentration (MIC) of carbapenem antibiotics ≤ 8 mg/L, combined anti-infective therapy may be more suitable
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4.
Selection of combined anti-infective treatment plan Reviewing the CHINET surveillance network in China, more than half of Enterobacteriaceae strains have MIC ≤ 8mg/L, which has laid a strong foundation for the application of combined anti-infective treatment plan
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But how to choose a combined anti-infective treatment plan to avoid the antagonistic effect and obtain a better synergistic effect? We need to first design experiments in vitro to clarify the fractional inhibitory concentration index (FICI) of antibiotics, so as to obtain a combination of antibiotics that can potentially produce synergistic effects in the host
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In vitro combined drug susceptibility tests are usually designed with a checkerboard method, measured by a microdilution method, and calculated the FICI value under the combination of the two drugs
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Usually, FICI≤0.
5 is regarded as a synergistic effect; 0.
5 to 1 is regarded as a partial synergistic effect; ≥4 is regarded as an antagonistic effect of the two groups of antibiotics
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It should be noted that although polymyxin-mediated/resistant Klebsiella pneumoniae are relatively rare, there is a risk of heterogeneous resistance to polymyxin, which will increase the risk of death in infected patients and should be avoided alone.
; Therefore, a combination therapy based on polymyxin drugs is recommended to reduce the risk of heterogeneous drug resistance and increase the success rate of treatment
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A net-like meta-analysis evaluated the synergistic bactericidal effects of different combination schemes on carbapenem-resistant gram-negative bacteria infections, and included more than 180 combination schemes from 136 studies
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The most commonly used combinations are polymyxins and carbapenems
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The results of the study showed that carbapenem combined with aminoglycosides/or combined with polymyxin B had a higher synergistic effect on CRKP
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In addition, a number of studies have shown the synergistic bactericidal effect of a carbapenem-based combination scheme on CRKP strains, especially for CRKP that produces KPC enzymes
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It should be noted that a prospective study completed recently was designed to analyze the sensitivity of strains to antimicrobial drugs and the synergistic effect analysis of fosfomycin combined with meropenem, and found that the combination of meropenem and fosfomycin has a significant synergistic effect
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So, can the combined anti-infective treatment plan also achieve synergistic effects under different resistance mechanisms? The answer is yes
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A retrospective CRE epidemiological drug susceptibility results conducted by foreign scholars showed that aztreonam alone had poor antibacterial activity against CRE that produces metalloenzymes
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For metalloenzyme-producing CRKP, carbapenem and tigecycline combined anti-infective treatment regimens show a higher synergistic effect in vitro
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Specifically: In the treatment of NDM-1 enzyme-producing CRE, carbapenem combined with aminoglycosides and tigecycline combined with amino sugars have a higher synergistic effect; IMP-producing CRE, carbapenem combined with more Colistin regimen, tigecycline combined with amino sugar regimen have a higher synergistic effect; for non-enzyme-producing resistance mechanism (porin deletion) CRKP, the research results show: tigecycline combined with amikacin regimen, carbon The penicillene joint program has a higher synergistic effect
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What is even more surprising is that some combination treatments can significantly reduce the MIC value of antibiotics while exerting a synergistic effect
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A study aimed at evaluating the in vitro antibacterial effects of colistin and meropenem and rifampicin on clinically isolated CRKP.
The broth dilution method and the checkerboard dilution method were used to determine the combined use of colistin B respectively.
A study on the minimum inhibitory concentration of meropenem and rifampicin against 20 clinically isolated CRKP and calculation of the partial inhibitory concentration index
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The results of the study showed that the synergistic effect of colistin B and meropenem was 55%, and the additive effect was 45%.
After colistin B and meropenem were used in combination, the MIC 50 of colistin and meropenem The MIC 90 is 1/4 of the single drug, and the MIC 50 and MIC 90 of meropenem are 1/32 and 1/4 of the single drug.
For CRKP, the combined use of meropenem and polymyxin B is synergistic.
The MIC is significantly reduced
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A prospective study aimed at analyzing the sensitivity of isolated strains to antibacterial drugs and the synergistic effect of fosfomycin and meropenem, including gram-negative strains resistant to β-lactams and colistin, the study found that meropenem The combined fosfomycin regimen has a synergistic effect on CRE, and the MIC value of the combined meropenem is at least 8 times lower
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In addition, domestic scholars have reported that the combination of polymyxin and rifampicin has a synergistic effect, and the MIC value of polymyxin after the combination is at least three times lower
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It can be seen that the reasonable combination of antibiotics may provide important ideas for clinically refractory infections
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5.
The choice of combined antibacterial treatment for severe infections The advent of tigecycline has diversified our choice of anti-infective treatment options, and has found a glimmer of hope for the treatment of CRE
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However, a prospective multi-center study of bloodstream infections caused by CRE found that tigecycline (including the combined regimen) did not achieve surprising effects, and the reason may be related to the tigecycline MIC of the strain
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Fortunately, the study aimed to clarify the clinical treatment results of different types of CRKP infections with different treatments has found that a combination of carbapenem antibiotics can effectively reduce the risk of death in patients with different types of CRKP infections
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A systematic review of 22 observational studies and randomized controlled studies was designed to compare the effects of colistin monotherapy and colistin-based combination therapy on carbapenem-resistant gram-negative bacteria infections in adult patients The results of the study found that the combination of polymyxin and carbapenem regimen for carbapenem-resistant gram-negative bacteria infections can significantly reduce the risk of death in patients
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Interestingly, the European Society for Infection and Clinical Microbiology (ESCMID) led a study on the combination treatment of carbapenem-resistant bacteria.
The study included a total of 141 hospitals in many European countries.
Carbapenem combination regimen (combined with polymyxin or tigecycline) as the main treatment regimen for combination therapy of carbapenem-resistant bacteria
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6.
The initiation and course of the combined anti-infective treatment program is aimed at patients with sepsis/septic shock.
Early application of antibiotics (less than 6 hours) can improve the prognosis of severely ill patients
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Similarly, the early initiation (within 1 day) of antibacterial therapy (mainly based on the combination regimen) to treat patients with bloodstream infections caused by KPC-KP can significantly reduce the risk of death
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An observational study conducted in two ICU wards in Italy included 102 patients with KPC-KP bacteremia who were hospitalized between January 2015 and December 2018, aiming to evaluate blood culture (BC) to initiate appropriate antibacterial Correlation between treatment time and 30-day mortality of patients
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The results of the study showed that timely antibacterial treatment (≤24h) was initiated to effectively reduce the 30-day risk of death in patients with KPC-KP bloodstream infection
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A longer (≥10 days) course of antibacterial treatment for CRE bloodstream infections has a higher survival rate for patients
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A prospective multi-center study of bloodstream infections caused by CRE in China found that the prognosis of CRE bloodstream infections treated with a course of antibacterial treatment less than 10 days is worse than that of an antibacterial course of ≥10 days
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However, the timing and duration of combined anti-infective treatment for infections caused by CRKP still need more high-quality studies to recommend
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 References: 1.
Renru Han, et al.
Dissemination of Carbapenemases (KPC, NDM, OXA-48, IMP, and VIM) Among Carbapenem-Resistant Enterobacteriaceae Isolated From Adult and Children Patients in China.
Front Cell Infect Microbiol.
2020 Jul 3;10:314.
3.
Thea Brennan-Krohn, et al.
New Strategies and Structural Considerations in Development of Therapeutics for Carbapenem-Resistant Enterobacteriaceae.
Transl Res.
2020 Jun;220:14-32.
4.
Mario Tumbarello , et al.
Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study.
Clin Infect Dis.
2021 Feb 22;ciab176.
5.
Renato Pascale, et al.
Use of meropenem in treating carbapenem-resistant Enterobacteriaceae infections.
Expert Rev Anti Infect Ther.
2019 Oct;17(10):819-827.
6.
Belén Gutiérrez-Gutiérrez, et al.
Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study.
Lancet Infect Dis.
2017 Jul;17(7):726-734.
7.
Xiaojuan Wang, et al.
Retrospective Observational Study from a Chinese Network of the Impact of Combination Therapy versus Monotherapy on Mortality from Carbapenem-Resistant Enterobacteriaceae Bacteremia.
Antimicrob Agents Chemother.
2018 Dec 21;63(1):e01511-18.
8.
Luigia Scudeller, et al.
Systematic review and meta -analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.
Int J Antimicrob Agents.
2021 May;57(5):106344.
9.
A Oliva, et al.
In vitro evaluation of different antimicrobial combinations against carbapenemase- producing Klebsiella pneumoniae:the activity of the double-carbapenem regimen is related to meropenem MIC value.
J Antimicrob Chemother 2017 Jul 1;72(7):1981-1984.
10.
Chaoe Zhou, et al.
Bloodstream Infections Caused by Carbapenem-Resistant Enterobacterales: Risk Factors for Mortality , Antimicrobial Therapy and Treatment Outcomes from a Prospective Multicenter Study.
Infect Drug Resist 2021 Feb 24;14:731-742.
11.
LS Tzouvelekis, et al.
Treating infections caused by carbapenemase-producing Enterobacteriaceae.
Clin Microbiol Infect 2014 Sep;20(9) :862-72.
12.
Oren Zusman, et al.
Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis.
J Antimicrob Chemother.
2017 Jan;72(1):29-39.
13.
L Papst, et al .
Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli:an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals.
Clin Microbiol Infect.
2018 Oct;24(10):1070-1076.
14.
Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC -producing Klebsiella pneumoniae.
Crit Care.
2020 Jan 30;24(1):29.
15.
Enbo Liu, et al.
In vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant Klebsiella pneumoniae with Different Resistance Mechanisms in China.
Infect Drug Resist.
2021 Mar 5; 14: 917-928.
Expert profile Guo Jun Chief physician of the Department of Respiratory and Critical Care Medicine, Beijing Tsinghua Chang Gung Memorial Hospital, Affiliated to Tsinghua University, Executive Director of the Department of Geriatrics, Associate Professor/Master's Tutor of Tsinghua University School of Medicine, Beijing Medical Association Member of the Respiratory and Critical Care Group of the Geriatrics Branch Member of the Middle-aged and Elderly Healthcare Branch of the Chinese Medical Promotion Association Member of the Respiratory Therapy Branch of the Beijing Infection Control and Disinfection Technology Association Expert from the Drug Evaluation Center of the National Food and Drug Administration Graduated from the Department of Internal Medicine of Peking Union Medical College.
Doctor of MedicineTime to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae.
Crit Care.
2020 Jan 30;24(1):29.
15.
Enbo Liu, et al.
In vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant Klebsiella pneumoniae with Different Resistance Mechanisms in China.
Infect Drug Resist.
2021 Mar 5;14: 917-928.
Introduction Executive Director, Department of Geriatrics, Associate Professor/Master's Supervisor, Tsinghua University School of Clinical Medicine, Member of the Respiratory and Critical Care Group of the Geriatrics Branch of the Beijing Medical Association Expert from the Drug Evaluation Center of the China Food and Drug Administration graduated from the Department of Internal Medicine, Peking Union Medical College, and received a doctorate in medicineTime to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae.
Crit Care.
2020 Jan 30;24(1):29.
15.
Enbo Liu, et al.
In vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant Klebsiella pneumoniae with Different Resistance Mechanisms in China.
Infect Drug Resist.
2021 Mar 5;14:917-928.
Expert profile Guo Jun, Chief physician of the Department of Respiratory and Critical Care Medicine, Beijing Tsinghua Chang Gung Memorial Hospital, Tsinghua University, Executive Director, Department of Geriatrics, Associate Professor/Master's Supervisor, Tsinghua University School of Clinical Medicine, Member of the Respiratory and Critical Care Group of the Geriatrics Branch of the Beijing Medical Association Expert from the Drug Evaluation Center of the China Food and Drug Administration graduated from the Department of Internal Medicine, Peking Union Medical College, and received a doctorate in medicineIn vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant Klebsiella pneumoniae with Different Resistance Mechanisms in China.
Infect Drug Resist.
2021 Mar 5;14:917-928.
Introduction Chief Physician of the Department of Critical Care Medicine, Executive Director of the Department of Geriatrics, Tsinghua University Clinical School Associate Professor/Master's Tutor Member of the Respiratory and Critical Care Group of the Geriatrics Branch of the Beijing Medical Association Member of the Respiratory Therapy Branch of the Technical Association Expert from the Drug Evaluation Center of the National Food and Drug Administration Graduated from the Department of Internal Medicine, Peking Union Medical College, and received a doctorate in medicineIn vitro and in vivo Effect of Antimicrobial Agent Combinations Against Carbapenem-Resistant Klebsiella pneumoniae with Different Resistance Mechanisms in China.
Infect Drug Resist.
2021 Mar 5;14:917-928.
Introduction Chief Physician of the Department of Critical Care Medicine, Executive Director of the Department of Geriatrics, Tsinghua University School of Clinical Medicine Associate Professor/Master's Tutor Member of the Respiratory and Critical Care Group of the Geriatrics Branch of the Beijing Medical Association Member of the Respiratory Therapy Branch of the Technical Association Expert from the Drug Evaluation Center of the National Food and Drug Administration Graduated from the Department of Internal Medicine, Peking Union Medical College, and received a doctorate in medicine
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"National Advanced Individual in Fighting the New Coronary Pneumonia Epidemic", "Beijing Advanced Worker", "Outstanding Communist Party Member of Beijing University"
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Selected in the "Beijing Hundred, Thousand, Thousand Talents Project" in 2020
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The sub-specialist specializes in the diagnosis and treatment of respiratory tract infectious diseases, interstitial lung diseases, chronic airway diseases in the elderly, connective tissue diseases-related lung diseases and other respiratory non-neoplastic diseases
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The main research directions are: pathogenic diagnosis and anti-infective treatment of lower respiratory tract infections
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He has published more than 30 academic papers in both Chinese and English.
As the host, he has undertaken scientific research tasks approved by the Beijing Municipal Natural Science Foundation (Haidian Original Innovation-Frontier Project), Tsinghua University (special independent scientific research international cooperation project) and Beijing Hospital Management Center
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This article is only used to provide scientific information to medical and health professionals, and does not represent the platform's position.
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5.
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6.
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