How effective is the combination of antibiotics for carbapenem-resistant gram-negative bacteria in vitro?

*For the reference of medical professionals, the drug resistance situation of gram-negative bacteria is severe.
How should we deal with it? Since the 21st century, due to the unreasonable use of antimicrobial drugs, the rate of bacterial resistance has increased year by year, and antimicrobial resistance has become a threat The global crisis of human health
.

Among them, enterobacteriaceae (CRE) represented by carbapenem-resistant Klebsiella pneumoniae (CRKP), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant abalone Acinetobacter (CRAB) and other multi-drug-resistant (MDR) or pan-drug-resistant (XDR) gram-negative bacteria infections are highly resistant to common antimicrobial drugs, and the types of antimicrobial drugs that can be selected clinically are very limited.
Cause great distress
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 The superiority of antibiotic combination therapy is still controversial.
In April 2021, Luigia SCUDELLER and others published a systematic review "Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-" in the International Journal of Antimicrobial Agents.
"negative bacilli", in order to predict the effectiveness of the antibiotic regimen from in vitro model studies, and provide stronger support for subsequent antibiotic selection plans for multi-drug resistant bacteria and further clinical trials
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 The rapid emergence and spread of MDR gram-negative bacteria (GNB) is considered a major public health problem
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Treatment options for carbapenem-resistant gram-negative bacteria (CR-GNB) are more limited
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In order to guide the research and development of new antibacterial drugs, the World Health Organization (WHO) released a list of priority carbapenem-resistant pathogens in 2017: mainly including Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter
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 So far, the development of new anti-CR-GNB antibacterial drugs in vitro is mainly tested in clinical trials, and they may often face the phenomenon of simultaneous carbapenem-sensitive bacterial infection
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Other types of antibacterial drugs (such as polymyxin, carbapenem, and aminoglycosides) are generally used alone in CR-GNB therapy or combined treatment strategies in some observational studies
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Combining two or more antibacterial drugs to treat CR-GNB is based on the principle that it can achieve higher bacterial killing rates and reduce the occurrence of resistance.
Although some studies have shown promising results, the aggregate data from the meta-analysis did not give antibacterial There is clear evidence that the combination of drugs is effective in the treatment of CR-GNB infection
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In addition, the results of rigorously designed clinical trials involving MDR-GNB infection are lacking, and compared with new drugs, the effectiveness of original antibacterial drugs cannot be confirmed
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 In an in vitro test, evaluating the synergy of bacterial killing and antibacterial drugs can be used to support the effectiveness of antibacterial combination therapy
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A recent meta-analysis of 26 clinical cases from 11 studies found that the synergy-guided antimicrobial combination and MDR-GNB infection patients (54% Pseudomonas aeruginosa, 27% Enterobacter, 19% Acinetobacter baumannii) The prognosis was significantly correlated (OR: 0.
47, 95% CI: 0.
21-1.
04)
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However, there are only two systematic reviews to evaluate the efficacy of antimicrobial combination therapy on CR-GNB, and only target specific pathogens and a limited number of antimicrobial drug dosages and programs
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The COHERENCE project aims to collect coherent and comprehensive analysis of the use of antimicrobial drugs in the treatment of severe infections caused by CR-GNB.
The project is commissioned by the Global Antibiotic Research and Development Partnership And the public evidence of clinical research, from a global perspective, provides evidence of the efficacy of using antibacterial drugs in the treatment of severe infections caused by CR-GNB
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This systematic review meta-analysis summarizes data from in vitro studies, from time-kill TK (Time-kill, TK) and pharmacokinetics/pharmacodynamics (PK/PD) studies to evaluate all antimicrobial combinations and doses for CRAB, CRPA , CRE in vitro activity
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 As part of the COHERENCE study, the review followed the Priority Reporting Entry (PRISMA) guidelines for systematic reviews and meta-analyses.
All the publications of Pubmed, Scopus and WOS were searched as of December 31, 2018, and included the combination of CR-GNB antibacterial drugs.
For all PK/PD and TK related studies, a systematic review and meta-analysis were conducted to evaluate the in vitro effectiveness of the CR-GNB antibiotic regimen
.

The initial endpoint is the in vitro synergy rate (Effective size ES: high ≥ 0.
75; medium 0.
35-0.
75; low ≤ 0.
35; none=0)
.

 This systematic review retrieved a total of 6849 articles, 439 full texts were evaluated, and finally included 136 studies (94 TK and 42 PK/PD articles)
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Types of pathogens and antibacterial treatment: 42 studies reported data on PK/PD (24 two-compartment models, 18 one-compartment models), 94 were TK studies, and 10 studies included the above-mentioned PK/PD and TK Aspects of research
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In terms of pathogens: 56 studies on Acinetobacter baumannii data, 54 studies on Klebsiella pneumoniae data, and 31 studies on Pseudomonas aeruginosa
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A total of 182 antibacterial drug combinations were studied in TK, with 94% dual antibacterial drugs and 5% triple antibacterial drugs
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In the PK/PD study, 21 antibacterial drugs belong to 12 categories, constituting 41 treatment options: 90% dual antibacterial drugs and 10% triple antibacterial drugs
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 Among 180 combinations of 136 studies, the most frequently analyzed combination is colistin combined with carbapenem
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There are limited data on ceftazidime/avibactam, ceftolozine/tazobactam and imipenem/raibactam, and the article gives the in vitro efficacy of different antimicrobial combinations according to different pathogens: ■ Bowman The following combinations of Acinetobacter show a high degree of synergy: (1) Multiple TK studies: Meropenem-polymyxin B/colistin combination (ES 0.
82, 0.
87), polymyxin-tigecycline combination ( ES 0.
89) and polymyxin-rifampicin combination (ES 0.
75); (2) Single study: colistin-trimethoprim/sulfamethoxazole combination (ES 1.
00), polymyxin B-A Mikacin combination (ES 1.
00) and imipenem-tigecycline combination (ES 0.
80); (3) PK/PD study: polymyxin-rifampicin combination (ES 0.
91) and imipenem -Tobramycin combination (ES 1.
00)
.

 ■ The following combinations of Klebsiella pneumoniae show high synergy rate: (1) Multiple TK studies: colistin-rifampicin combination (ES 1.
00), colistin-imipenem/dolipenem combination (ES 1.
00), imipenem/meropenem-amikacin combination (ES 1.
00); (2) PK/PD study: ceftazidime/avibactam-aztreonam combination (ES 1.
00), polymyxa Element-fosfomycin combination (ES 1.
00)
.

 ■ Pseudomonas aeruginosa (1) A number of TK studies showed a moderate synergy rate: ceftizide/tazobactam-polymyxin combination (ES 0.
50), colistin-imipenem combination (ES 0.
67) and meropenem-amikacin combination (ES 0.
43), colistin-meropenem combination and tobramycin-imipenem combination also showed moderate synergy; (2) high in PK/PD study Synergy rate: imipenem-amikacin combination (ES 1.
00); (3) Moderate synergy in PK/PD studies: colistin-dolipenem combination
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 This is the first systematic review and meta-analysis of in vitro studies on the efficacy of more than 180 combination therapies on three different CR-GNBs
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The article chose in vitro methods based on kill curves, especially TK and PK/PD studies
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These two methods have significant advantages in studying the effectiveness of combination therapies
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TK research is one of the most commonly used, most standardized, and repeatable static combination experiment methods
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The PK/PD model can simulate the killing and regrowth of bacteria after exposure to human drugs, and it is also considered to be an accurate and informative in vitro method for studying antimicrobial combinations
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 This systematic review highlights the promising results of selected in vitro antibacterial drug combinations (including polymyxin-tigecycline combination and polymyxin-rifampicin combination against Acinetobacter baumannii, polymyxin- The fosfomycin combination and the polymyxin-rifampicin combination target Klebsiella pneumoniae, the carbapenem-aminoglycoside combination and the carbapenem-colistin combination target Pseudomonas aeruginosa)
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For Acinetobacter baumannii, the colistin-rifampicin combination showed consistent synergy in pharmacokinetic/pharmacodynamic (PK/PD) and TK studies, while polymyxin and carbapenem Or the synergy between tigecycline is not obvious
.

The correlation between colistin and rifampicin is very promising.
In the previous two randomized controlled trials (RCT) in humans, although there was no report on the mortality rate, the combination can increase the microorganisms of Acinetobacter baumannii Clearance rate
.

Although the anti-infective benefit of polymyxin-rifampicin against Klebsiella pneumoniae has not been evaluated in the RCT of this pathogen, this combination also shows significant synergy
.

Regarding Klebsiella pneumoniae, fosfomycin is a potential and promising option.
The combination with polymyxin not only shows a synergistic effect, but also significantly increases the bactericidal activity of polymyxin
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Finally, the combined application of aminoglycoside and imipenem showed significant synergy (such as imipenem and amikacin) and bactericidal activity against Pseudomonas aeruginosa (such as imipenem, amikacin) Or tobramycin)
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Although this combination therapy strategy is often used as an empirical treatment for blood infections in clinical practice, the nephrotoxicity and limited lung penetration of aminoglycoside drugs significantly limit the clinical application of this combination therapy program
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 The summary data does have some shortcomings in the analysis process of in vitro research
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Specifically, for several combinations, due to the limited number of available reports for evaluating in vitro synergy, and the limited comparability between available reports, no final conclusion can be drawn
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Few high-quality TK and PK/PD studies have been conducted on antibacterial drug combinations, including antibacterial drugs frequently used in clinical practice recently on the market
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Even in the combination of meta-analysis, high research variability hinders useful explanations that can be summarized
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 Because CR-GNB has a tendency to acquire multiple antimicrobial resistance, the development of in vitro research is very important for discovering potential synergistic antimicrobial combination strategies during clinical trials
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The main advantages of in vitro research, especially the PK/PD model, including the possibility of exploring effective antibacterial programs by adjusting the amount of bacterial inoculation and extending the research time, are advantages that clinical research institutes cannot match
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However, the lack of validation of clinical data is still the main limitation to explain the significance of in vitro synergistic effects
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In addition, the clinician's understanding of the correct interpretation and limitations of the in vitro results is crucial
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The results from in vitro research data can only prove the potential use of existing methods and explore the efficacy of antibacterial drug combinations, thereby helping to optimize collaborative trials, which may also promote clinical research at the individual and strain specific levels
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 The drug resistance situation of gram-negative bacteria in China is severe, and clinical anti-infection treatment is facing major challenges.
Once CRE, CRPA and other MDR and XDR gram-negative bacteria infections occur, the options for treatment are very limited
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The results of this review encourage high-quality in vitro studies to explore potential promising antibacterial combinations for clinical practice, and guide treatment options in future randomized controlled trials to improve anti-CR-GNB treatment options
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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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