Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: antibacterials for systemic use, carbapenems
ATC code: J01DH02
Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
Similar to other beta-lactam antibacterial agents, the time that meropenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for approximately 40% of the dosing interval. This target has not been established clinically.
Bacterial resistance to meropenem may result from: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) (2) reduced affinity of the target PBPs (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyse carbapenems.
Localised clusters of infections due to carbapenem-resistant bacteria have been reported in the European Union.
There is no target-based cross-resistance between meropenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to more than one class of antibacterials agents when the mechanism involved include impermeability and/or an efflux pump(s).
European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented below.
EUCAST clinical MIC breakpoints for meropenem (2013-02-11, v 3.1):
| Organism | Susceptible (S) (mg/l) | Resistant (R) (mg/l) |
|---|---|---|
| Enterobacteriaceae | ≤2 | >8 |
| Pseudomonas spp. | ≤2 | >8 |
| Acinetobacter spp. | ≤2 | >8 |
| Streptococcus groups A, B, C, and G | note 6 | note 6 |
| Streptococcus pneumoniae1 | ≤2 | >2 |
| Viridans group streptococci2 | ≤2 | >2 |
| Enterococcus spp. | -- | -- |
| Staphylococcus spp. | note 3 | note 3 |
| Haemophilus influenza1,2 and Moraxella catarrhalis2 | ≤2 | >2 |
| Neisseria meningitidis2,4 | ≤0.25 | >0.25 |
| Gram-positive anaerobes except Clostridium difficile | ≤2 | >8 |
| Gram-negative anaerobes | ≤2 | >8 |
| Listeria monocytogenes | ≤0.25 | >0.25 |
| Non-species related breakpoints5 | ≤2 | >8 |
1 Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25/l (Susceptible) and 1 mg/l (Resistant).
2 Isolates with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the identification is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC values above the current resistant breakpoint they should be reported resistant.
3 Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.
4 Breakpoints relates to meningitis only.
5 Non-species related breakpoints have been determined using PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints. Non species related breakpoints are based on the following dosages: EUCAST breakpoints apply to meropenem 1000 mg x 3 daily administered intravenously over 30 minutes as the lowest dose. 2 g x 3 daily was taken into consideration for severe infections and in setting the I/R breakpoint.
The beta-lactam susceptibility of streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.
Isolates may be reported as R without prior testing.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
The following table of pathogens listed is derived from clinical experience and therapeutic guidelines.
Gram-positive aerobes:
Enterococcus faecalis$
Staphylococcus aureus (methicillin-susceptible)£
Staphylococcus species (methicillin-susceptible) 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-negative anaerobes:
Bacteroides caccae
Bacteroides fragilis group
Prevotella bivia
Prevotella disiens
Gram-positive aerobes:
Enterococcus faecium$†
Gram-negative aerobes:
Acinetobacter species
Burkholderia cepacia
Pseudomonas aeruginosa
Gram-negative aerobes:
Stenotrophomonas maltophilia
Legionella species
Chlamydophila pneumoniae
Chlamydophila psittaci
Coxiella burnetii
Mycoplasma pneumoniae
Species that show natural intermediate susceptibility
$ All methicillin-resistant staphylococci are resistant to meropenem
£ Resistance rate ≥50% in one or more EU countries.
† Resistance rate ≥50% in one or more EU countries.
Glanders and melioidosis: Use of meropenem in humans is based on in vitro B.mallei and B. pseudomallei susceptibility data and on limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.
In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11-27 l) and the mean clearance is 287 ml/min at 250 mg falling to 205 ml/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean Cmax values of approximately 23, 49 and 115 μg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153 μg.h/ml. After infusion over 5 minutes Cmax values are 52 and 112 μg/ml after 500 and 1000 mg doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.
A study of 12 patients administered meropenem 1000 mg 8 hourly post-surgically for intra-abdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 27 l.
The average plasma protein binding of meropenem was approximately 2% and was independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30 minutes infusion. Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates.
Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.
Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50–75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.
Renal impairment results in higher plasma AUC and longer half-life for meropenem. There were AUC increases of 2.4 fold in patients with moderate impairment (CrCL 33-74 ml/min), 5 fold in severe impairment (CrCL 4-23 ml/min) and 10 fold in haemodialysis patients (CrCL <2 ml/min) when compared to healthy subjects (CrCL >80 ml/min). The AUC of the microbiologically inactive ring opened metabolite was also considerably increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and severe renal impairment (see section 4.2).
Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4 times higher that in anuric patients.
A study in patients with alcoholic cirrhosis shows no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.
Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance and age.
The pharmacokinetics in infants and children with infection at doses of 10, 20 and 40 mg/kg showed Cmax values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those observed in adults in all but the youngest subjects (<6 months t1/2 1.6 hours). The mean meropenem clearance values were 5.8 ml/min/kg (6-12 years), 6.2 ml/min/kg (2-5 years), 5.3 ml/min/kg (6-23 months) and 4.3 ml/min/kg (2-5 months). Approximately 60% of the dose is excreted in urine over 12 hours as meropenem with a further 12% as metabolite. Meropenem concentrations in the CSF of children with meningitis are approximately 20% of concurrent plasma levels although there is significant inter-individual variability.
The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater clearance in neonates with higher chronological or gestational age with an overall average half-life of 2.9 hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg 8 hourly achieved 60% T>MIC for P. aeruginosa in 95% of pre-term and 91% of full term neonates.
Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma clearance, which correlated with age-associated reduction in creatinine clearance, and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment (see section 4.2).
Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was seen in mice and dogs only at doses of 2000 mg/kg and above after a single administration and above and in monkeys at 500 mg/kg in a 7-day study.
Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1000 mg/kg.
The IV LD50 of meropenem in rodents is greater that 2000 mg/kg.
In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red cell parameters in dogs.
There was no evidence of mutagenic potential in a conventional test battery and no evidence of reproductive toxicity including teratogenic potential in studies in rats up to 750 mg/kg and in monkeys up to 360 mg/kg.
There was increased evidence of abortions at 500 mg/kg in a preliminary study in monkeys.
There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies.
The sole metabolite of meropenem had a similar profile of toxicity in animal studies.
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