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    Home > Active Ingredient News > Infection > "Merro" or "Imine", how to choose carbapenems reasonably?

    "Merro" or "Imine", how to choose carbapenems reasonably?

    • Last Update: 2022-06-06
    • Source: Internet
    • Author: User
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    *For medical professionals to read and refer to how to choose carbapenems, you will understand after reading this article! Carbapenems are β-lactam antibacterial drugs with broad antibacterial spectrum, strong bactericidal activity and wide clinical use; they are the first-line drugs for clinical treatment of severe, mixed infections and drug-resistant bacteria
    .

    Studies have shown that infections caused by gram-negative bacteria account for 65.
    7%-73% [1], which is significantly higher than that of gram-positive bacteria
    .

     Carbapenems have strong antibacterial effects on Gram-negative bacteria, especially for infections caused by multi-drug resistant (MDR) and pan-drug-resistant Gram-negative bacteria (XDR-GNB), carbapenems are widely respected
    .

    For example, for pulmonary infections caused by extended-spectrum β-lactamases (ESBLs) and cephalosporinase (Ampc)-producing Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, etc.
    ), carbapenems The clinical efficacy was satisfactory
    .

     Thiomycin was the first carbapenem to come out and was eliminated due to poor chemical stability
    .

    By modifying and rectifying the chemical structure of thiomycin, a new generation of carbapenems, such as imipenem, has been developed
    .

    With the continuous development of medicinal chemistry, panipenem, meropenem, ertapenem and other drugs have been added to the carbapenem family, providing more options for clinical diagnosis and treatment of bacterial infections
    .

     First, a brief review of the development and clinical progress of carbapenems is shown in Table 1
    .

     Table 1 R&D overview and clinical progress of carbapenems [2-3] Carbapenems commonly used in China are imipenem, meropenem, panipenem, biapenem and ertapenem
    .

    Faced with such a huge carbapenem family, what are the trends in clinical drug selection? What is the difference between carbapenems? Bring your questions, please read the analysis later! One structure determines the nature: different chemical structures and stability differences The early developed imipenem and panipenem, because of their lack of 1-β-methyl group in their chemical structures (see the red circle position in Figure 1), are harmful to the kidneys.
    Dehydropeptidase 1 (DHP-1) has poor stability and is easily decomposed by DHP-1 to produce nephrotoxic metabolites, which affects the antibacterial efficacy
    .

    Therefore, imipenem and panipenem are used in combination with cilastatin and betamirone respectively to form a compound preparation
    .

     Figure 1 The chemical structure of common carbapenems The subsequent development of meropenem, ertapenem, etc.
    have added methyl substitution at the No.
    1 carbon atom (see the blue circle position in Figure 1), and the stability of DHP-1 increase
    .

    Therefore, meropenem, ertapenem, biapenem, and doripenem do not need to be combined with DHP-1 inhibitors and can be used directly
    .

    2.
    Comparison of antibacterial spectrum: similar and different ● Similarities: as shown in Table 2
    .

    Table 2 ● Differences: There are many types of carbapenems, and there are differences in the antibacterial spectrum of ertapenem, imipenem and meropenem; see Table 3 [4] for details
    .

    Note in Table 3: "Uncertain" means that both sensitive or resistant may be possible, and the actual drug susceptibility report should be referred to for judgment
    .

    Comparison of three antibacterial efficacy ➤Comparison of meropenem and imipenem [5]: Gram-negative bacteria: Meropenem's antibacterial efficacy is 4-16 times that of imipenem; Gram-positive bacteria: imipenem is meropenem's 2-4 times
    .

    ➤The carbapenems mentioned above are summarized as follows according to the type of pathogenic bacteria [5-7]: Pseudomonas aeruginosa: meropenem > imipenem (biapenem) > panipenem Enterobacteriaceae: meropenem > imipenem (biapenem) > panipenem anaerobic bacteria: biapenem (ertapenem, meropenem) ≥ imipenem Gram-positive bacteria: imine Penem (panipenem) > biapenem > meropenem Acinetobacter baumannii: biapenem > imipenem > meropenem > panipenem four drug safety Generally speaking, carbapenem Classes are more secure
    .

    However, according to the data of the U.
    S.
    Food and Drug Administration's Adverse Drug Event Surveillance System (FAERS) from 2015 to 2018, there were 5,899 adverse drug events involving carbapenems during the period, and serious adverse drug reactions accounted for 41.
    24%; South can cause nervous system disorders [8]
    .

     Carbapenems can interact with lambda-aminobutyric acid type alpha receptors (GABAa) and have a risk of causing seizures
    .

    Compared with panipenem and meropenem, imipenem has a greater risk of induced epilepsy [9]
    .

    Therefore, medication monitoring should still be carried out during the actual medication process
    .

     Five Current Status of Infections Caused by Carbapenem-Resistant Enterobacteriaceae (CRE) Although carbapenems were once evaluated as "the last line of defense against bacterial infections"! However, with the intensification of the aging of the population in China, the demand for medical treatment and hospital admission of patients with chronic diseases has increased, and the pressure on the diagnosis and treatment of bacterial infectious diseases has increased year by year
    .

    In recent years, the detection rate of CRE has increased significantly.
    In 2021, the resistance rate of Klebsiella pneumoniae to meropenem was 21.
    9%, an increase of nearly 10 times compared with 2005 (2.
    9%) [1]
    .

     Enterobacteriaceae acquired drug resistance by producing carbapenems, among which KPC molds were the most common in China; NDM and OXA molds were also detected
    .

    A research team in my country obtained 935 CRE strains from enrolled patients (including children and adults) and sequenced their genes.
    The results are shown in Figure 2[10]
    .

    Figure 2 Carbapenemase distribution of CRE strains isolated from children and adults As shown in Figure 2, the carbapenemase-resistant genes carried by CRE strains in children and adults are mostly KPC (children: 35.
    1% , 70.
    3% of adults), among which the main drug resistance genes of Escherichia coli and Klebsiella pneumoniae are NDM and KPC, respectively
    .

     6.
    Can carbapenems still be useful for infections caused by CRE? Figure 3 is a sputum culture and drug susceptibility report of a patient with lung infection, suggesting that the patient was infected with carbapenem-resistant Klebsiella pneumoniae (CRKP, which belongs to the category of CRE)
    .

    This patient is resistant to imipenem, meropenem, and ertapenem, so are carbapenems still clinically meaningful to the patient? Figure 3 A drug susceptibility report of a patient infected with CRKP The premise of the use of carbapenems in the treatment of CRE [11]: the MIC of carbapenems in the drug susceptibility report is ≤ 8; imipenem and meropenem are drugs that can be considered clinically , the daily dose of ertapenem (1g/d) is low and not suitable for CRE strains
    .

    In clinical practice, high-dose meropenem (2g q8h) and slow intravenous infusion are generally selected (the infusion time is extended to 2-3h)
    .

    Carbapenems should be used in combination with drugs such as polymyxin and tigecycline
    .

    Therefore, this patient is not recommended to choose carbapenems for anti-infection, and more appropriate to choose drugs such as polymyxin and tigecycline for treatment
    .

    References: [1] China Antimicrobial Resistance Surveillance Network (CHINET) 2021 Report [2] Mouton JW, Touzw DJ, Horrevorts AM, Vinks AA.
    Comparative pharmacokinetics of the carbapenems: clinical implications.
    Clin Pharmacokinet.
    2000 Sep;39( 3): 185-201.
    [3] Bassetti M, Nicolini L, Esposito S, Righi E, Viscoli C.
    Current status of newer carbapenems.
    Curr Med Chem.
    2009;16(5):564-75.
    [4]El -Gamal MI, Oh CH.
    Current status of carbapenem antibiotics.
    Curr Top Med Chem.
    2010;10(18):1882-97.
    [5]Bonfiglio G, Russo G, Nicoletti G.
    Recent developments in carbapenems.
    Expert Opin Investig Drugs .
    2002 Apr;11(4):529-44.
    doi: 10.
    1517/13543784.
    11.
    4.
    529.
    [6]Mikamo H, Sato Y, Hayasaki Y, Tamaya T.
    In vitro and in vivo antibacterial activities of biapenem in the fields of obstetrics and gynecology.
    Chemotherapy.
    2000 Mar-Apr;46(2):95-9.
    [7]El-Gamal MI, Brahim I, Hisham N, Aladdin R, Mohammed H, Bahaaeldin A.
    Recent updates of carbapenem antibiotics.
    Eur J Med Chem.
    2017 May 5;131:185-195.
    [8]Ge W, Hu H, Li C, Wang L, Xia J.
    Safety profile of carbapenems: Data mining of the FDA adverse events reporting system.
    Int J Clin Pharmacol Ther.
    2021 Sep;59(9):594-602.
    [9]Hara, K.
    ; Hiraga, Y.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509-531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D, Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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 .
    [11] Wang Minggui.
    Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of extensively drug-resistant gram-negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017, 17(1):11.
      2017 May 5;131:185-195.
    [8]Ge W, Hu H, Li C, Wang L, Xia J.
    Safety profile of carbapenems: Data mining of the FDA adverse events reporting system.
    Int J Clin Pharmacol Ther.
    2021 Sep;59(9):594-602.
    [9]Hara, K.
    ; Hiraga, Y.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509 -531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D, Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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.
    [11]Wang Minggui.
    XDR Gram Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017, 17(1):11.
    2017 May 5;131:185-195.
    [8]Ge W, Hu H, Li C, Wang L, Xia J.
    Safety profile of carbapenems: Data mining of the FDA adverse events reporting system.
    Int J Clin Pharmacol Ther.
    2021 Sep;59(9):594-602.
    [9]Hara, K.
    ; Hiraga, Y.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509 -531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D, Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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.
    [11]Wang Minggui.
    XDR Gram Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017, 17(1):11.
    Safety profile of carbapenems: Data mining of the FDA adverse events reporting system.
    Int J Clin Pharmacol Ther.
    2021 Sep;59(9):594-602.
    [9]Hara, K.
    ; Hiraga, Y.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509-531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D, Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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.
    [11]Wang Minggui.
    Laboratory diagnosis, antimicrobial therapy and nosocomial infection control of extensively drug-resistant gram-negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017 , 17(1):11.
    Safety profile of carbapenems: Data mining of the FDA adverse events reporting system.
    Int J Clin Pharmacol Ther.
    2021 Sep;59(9):594-602.
    [9]Hara, K.
    ; Hiraga, Y.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509-531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D, Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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.
    [11]Wang Minggui.
    Laboratory diagnosis, antimicrobial therapy and nosocomial infection control of extensively drug-resistant gram-negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017 , 17(1):11.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509-531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D , Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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.
    [11]Wang Minggui.
    Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of extensively drug-resistant gram-negative bacterial infection: Chinese expert consensus[J].
    Journal of and Chemotherapy, 2017, 17(1):11.
    ; Omichi, M.
    A Comparative study of panipenem/betamipron and imipenem/cilastatin in bacterial pneumonia.
    Chemotherapy, 1992, 40, 509-531.
    [10]Han R, Shi Q, Wu S, Yin D, Peng M, Dong D , Zheng Y, Guo Y, Zhang R, Hu F; China Antimicrobial Surveillance Network (CHINET) Study Group.
    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.
    [11]Wang Minggui.
    Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of extensively drug-resistant gram-negative bacterial infection: Chinese expert consensus[J].
    Journal of and Chemotherapy, 2017, 17(1):11.
    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.
    [11]Wang Minggui.
    Broad Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of drug-resistant Gram-negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017, 17(1):11.
    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.
    [11]Wang Minggui.
    Broad Laboratory diagnosis, antimicrobial treatment and nosocomial infection control of drug-resistant Gram-negative bacterial infection: Chinese expert consensus [J].
    Chinese Journal of Infection and Chemotherapy, 2017, 17(1):11.
     
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