Antibacterials for systemic use, carbapenems. ATC Code:
Meropenem is a carbapenem antibiotic for parenteral use, that is stable to human dehydropeptidase-I (DHP-I). It is structurally similar to imipenem.
Mechanism of action:
Meropenem exerts its bactericidal action by interfering with bacterial cell wall synthesis. The ease with which it penetrates bacterial cells, its high level of stability to most serine β-lactamases and its high affinity for multiple Penicillin Binding Proteins (PBPs) explain the potent bactericidal activity of meropenem against a broad spectrum of aerobic and anaerobic bacteria. The bactericidal concentrations are generally within one doubling dilution of the minimum inhibitory concentrations (MICs).
Meropenem is stable in susceptibility tests and these tests can be performed using the normal routine systems. In vitro tests show that meropenem can act synergistically with various antibiotics. It has been demonstrated both in vitro and in vivo that meropenem has a post-antibiotic effect against Gram-positive and Gram-negative organisms.
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.
Mechanisms 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).
European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented as follows. (See Table 2.)
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.
Commonly susceptible species: 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).
Commonly susceptible species: 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.
Commonly susceptible species: Gram-positive anaerobes: Clostridium perfringens
, Peptoniphilus asaccharolyticus
species (including P. micros
, P anaerobius
, P. magnus
Commonly susceptible species: Gram-negative anaerobes: Bacteroides caccae
, Bacteroides fragilis
, 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
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 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.
In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg and the mean clearance is 239 mL/min at 500 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. 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 β-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 Dosage & Administration).
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 has shown 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 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 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 Dosage & Administration).
Toxicology: Preclinical safety data:
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.
Meropenem is generally well tolerated by the CNS. Effects were seen only at very high doses of 2000 mg/kg and above.
The i.v. 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 small decrease in red cell parameters and an increase in liver weight in dogs at 500 mg/kg.
There was no evidence of mutagenic potential in the 5 tests conducted and no evidence of reproductive toxicity including teratogenic potential in studies at the highest possible level 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 intramuscular formulation caused reversible injection site necrosis.
The sole metabolite of meropenem had a similar low profile of toxicity in animal studies.