antibacterials for systemic use, carbapenems. ATC code:
Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DHP-1) and therefore, does not require the addition of an inhibitor of DHP-1.
Mechanism of action:
Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine β-lactamases and its marked affinity for multiple Penicillin Binding Proteins (PBPs) explain the potent bactericidal action of meropenem against a broad spectrum of aerobic and anaerobic bacteria. Minimum bactericidal concentrations (MBC) are commonly the same as the minimum inhibitory concentrations (MIC). For 76% of the bacteria tested, the MBC:MIC ratios were 2 or less.
Meropenem is stable in susceptibility tests and these tests can be performed using normal routine methods. In vitro
tests show that meropenem acts synergistically with various antibiotics. It has been demonstrated both in vitro
and in vivo
that meropenem has a post-antibiotic effect.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship:
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.
Mechanism of resistance:
Bacterial resistance to meropenem may result from one or more factors: (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 β-lactamases that can hydrolyse carbapenems.
Localised clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.
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 antibacterial agents when the mechanism involved include impermeability and/or an efflux pump(s).
A 30 minute intravenous infusion of a single dose of Meronem in healthy volunteers results in peak plasma levels of approximately 11 μg/ml for the 250 mg dose, 23 μg/ml for the 500 mg dose and 49 μg/ml for the 1 g dose.
However, there is no absolute pharmacokinetic proportionality with the administered dose both as regards Cmax and AUC. Furthermore, a reduction in plasma clearance from 239 to 205 ml/min for the range of dosage 500 mg to 2 g has been observed.
A 5 minute intravenous bolus injection of Meronem in healthy volunteers results in peak plasma levels of approximately 52 μg/ml for the 500 mg dose and 112 μg/ml for the 1 g dose.
After an IV dose of 500 mg, plasma levels of meropenem decline to values of 1 μg/ml or less, 6 hours after administration.
When multiple doses are administered at 8 hourly intervals to subjects with normal renal function, accumulation of meropenem does not occur.
In subjects with normal renal function, meropenem's elimination half-life is approximately 1 hour.
Plasma protein binding of meropenem is approximately 2%.
Approximately 70% of the administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 μg/ml are maintained for up to 5 hours after the administration of a 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1g administered every 6 hours in volunteers with normal renal function.
The only metabolite of meropenem is microbiologically inactive.
Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid of patients with bacterial meningitis, achieving concentrations in excess of those required to inhibit most bacteria.
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 t½ 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 patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment.
Pharmacokinetic studies in the elderly have shown a reduction in plasma clearance of meropenem which correlated with age-associated reduction in creatinine clearance.
Pharmacokinetic studies in patients with liver disease have shown no effects of liver disease on the pharmacokinetics of meropenem.
Toxicology: Pre-clinical Safety Data:
Animal studies indicate that meropenem is well tolerated by the kidney. In animal studies meropenem has shown nephrotoxic effects, only at high dose levels (500 mg/kg).
Effects on the CNS; convulsions in rats and vomiting in dogs, were seen only at high doses (>2000 mg/kg).
For an IV dose the LD50
in rodents is greater than 2000 mg/kg. In repeat dose studies (up to 6 months) only minor effects were seen including a small decrease in red cell parameters and an increase in liver weight in dogs treated with doses of 500 mg/kg.
There was no evidence of mutagenic potential in the 5 tests conducted and no evidence of reproductive and teratogenic toxicity in studies at the highest possible doses in rats and monkeys; the no effect dose level of a (small) reduction in F1
body weight in rat was 120 mg/kg.
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.
European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing and disk diffusion testing are presented in the following table. (See Table 1.)
Click on icon to see table/diagram/image
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 susceptibility to meropenem of a given clinical isolate should be determined by standard methods. Interpretations of test results should be made in accordance with local infectious diseases and clinical microbiology guidelines.
The antibacterial spectrum of meropenem includes the following species, based on clinical experience and therapeutic guidelines.
Gram-positive aerobes: Enterococcus faecalis
(note that E. faecalis
can naturally display intermediate susceptibility), Staphylococcus aureus
(methicillin-susceptible strains only: methicillin-resistant staphylococci including MRSA are resistant to meropenem), Staphylococcus
species including Staphylococcus epidermidis
(methicillin-susceptible strains only: methicillin-resistant staphylococci including MRSE are resistant to meropenem), Streptococcus agalactiae
(Group B streptococcus), Streptococcus milleri
group (S. anginosus, S. constellatus
, and S. intermedius
), Streptococcus pneumoniae, Streptococcus pyogenes
(Group A streptococcus).
Gram-negative aerobes: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.
Anaerobic bacteria: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus
including P. micros, P anaerobius, P. magnus).
Bacteroides caccae, Bacteroides fragilis
group, Prevotella bivia, Prevotella disiens.
Species for which acquired resistance may be a problem: Gram-positive aerobes: Enterococcus faecium
can naturally display intermediate susceptibility even without acquired resistance mechanisms.)
Species for which acquired resistance may be a problem: Gram-negative aerobes: Acinetobacter
species, Burkholderia cepacia, Pseudomonas aeruginosa.
Inherently resistant organisms: Gram-negative aerobes: Stenotrophomonas maltophilia, Legionella
Other inherently resistant organisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.
The published medical microbiology literature describes in-vitro meropenem-susceptibilities of many other bacterial species. However the clinical significance of such in-vitro findings is uncertain. Advice on the clinical significance of in-vitro findings should be obtained from local infectious diseases and clinical microbiology experts and local professional guidelines. Meropenem and imipenem have a similar profile of clinical utility and activity against multiresistant bacteria. However, meropenem is intrinsically more potent against Pseudomonas aeruginosa
and may be active in vitro
against imipenem-resistant strains.
Meropenem is active in vitro
against many strains resistant to other β-lactam antibiotics. This is explained in part by enhanced stability to β-lactamases. Activity in vitro
against strains resistant to unrelated classes of antibiotics such as aminoglycosides or quinolones is common.