Pharmacological properties
Pharmacodynamics. Meropenem has a bactericidal effect by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria by binding to penicillin-binding proteins (PBPs).
As with other beta-lactam antibacterial agents, the time at which meropenem concentrations exceeded the MIC (T MIC) showed a high degree of correlation with efficacy. In preclinical models, meropenem demonstrated activity at plasma concentrations exceeding the MIC for the infecting organisms by approximately 40% of the dosing interval. This target value has not been established clinically.
Bacterial resistance to meropenem may arise as a result of: 1) decreased permeability of the outer membrane of Gram-negative bacteria (due to decreased porin production); 2) decreased affinity for target PBPs; 3) increased expression of efflux pump components; and 4) production of beta-lactamases that can hydrolyze carbapenems.
Cases of infectious diseases caused by bacteria resistant to carbapenems have been reported in the European Union.
There is no cross-resistance between meropenem and drugs belonging to the quinolone, aminoglycoside, macrolide and tetracycline classes, taking into account the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial drugs when the mechanism involved involves cell membrane impermeability and/or the presence of efflux pump(s).
The MIC breakpoints that have been established in clinical trials by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are listed below.
microorganism Susceptible (S), mg/l Resistant (R), mg/l
| Enterobacteriaceae | ≤2 | 8 |
| Pseudomonas | ≤2 | 8 |
| Acinetobacter | ≤2 | 8 |
| Streptococcus, groups A, B, C, G | ≤2 | 2 |
| Streptococcus pneumoniae 1 | ≤2 | 2 |
| other streptococci | 2 | 2 |
| Enterococcus | - | - |
| Staphylococcus 2 | Note 3 | Note 3 |
| Haemophilus influenzae 1 and Moraxella catarrhalis | ≤2 | 2 |
| Neisseria meningitidis 2.4 | ≤0.25 | 0.25 |
| Gram-positive anaerobes | ≤2 | 8 |
| Gram anaerobes | ≤2 | 8 |
| Limit values not related to microorganism species 5 | ≤2 | 8 |
|
1 The meropenem breakpoint for Streptococcus pneumoniae and Haemophilus influenzae in meningitis is 0.25/L mg/L.
2 Strains with MIC values above the S/R breakpoint are very rare or have not been reported to date. Identification and antimicrobial susceptibility testing for any such isolate should be repeated and, if confirmed, the isolate should be sent to a reference laboratory. Until clinical response data are available for verified isolates with MIC values above the current resistance breakpoints, isolates should be recorded as resistant.
3 Susceptibility of staphylococci to meropenem is predicted based on methicillin susceptibility data.
4 The breakpoint for meropenem for Neisseria meningitidis applies only to meningitis.
5 The species-neutral breakpoint is based primarily on pharmacokinetic and pharmacodynamic data and is not dependent on the distribution of MICs among individual species. It is intended for use with species not listed in the table and footnotes.
"-" Susceptibility testing is not recommended as the species is a poor target for drug treatment.
The prevalence of acquired resistance may vary geographically and over time for individual species, therefore it is advisable to rely on local information on resistance patterns, especially in the treatment of severe infections. When necessary, when the local prevalence of resistance is such that the benefit of the drug in at least some types of infections is questionable, specialist advice should be sought.
The following lists pathogenic microorganisms based on clinical experience and therapeutic protocols for treating diseases.
Typically sensitive species
Gram-positive aerobes: Enterococcus faecalis 6, Staphylococcus aureus (methicillin) 7, Staphylococcus species (methicillin), including Staphylococcus epidermidis, Streptococcus agalactiae (group B), Streptococcus milleri group (S. anginosus, S. constellatus and S. intermedius), Streptococcus pneumoniae, Streptococcus pyogenes (group A). Gram-negative aerobes: Citrobacter freudii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitides, Proteus mirabilis, Proteus vulgaris, Serratia marcescens. Gram-positive anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus species (including P. micros, P. anaerobius, P. magnus). Gram anaerobes: Bacteroides caccae, Bacteroides fragilis group, Prevotella bivia, Prevotella disiens.
Species for which acquired resistance may be a problem
Gram-positive aerobes: Enterococcus faecium 6.8. Gram-negative aerobes: Acinetobacter species, Burkholderia cepacia, Pseudomonas aeruginosa.
Inherently resistant microorganisms
Gram-negative aerobes: Stenotrophomonas maltophilia, Legionella species.
Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.
6 Species that have shown natural intermediate sensitivity.
7 All methicillin-resistant staphylococci are resistant to meropenem.
Pharmacokinetics. In healthy subjects, T½ from plasma is about 1 hour; the mean volume of distribution is
