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Pharmacology: Pharmacodynamics: Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DHP-1). It is structurally similar to imipenem.
Meropenem exerts its bactericidal action by interfering with 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 the penicillin-binding proteins (PBPs) explain the potent bactericidal action of meropenem against a broad spectrum of aerobic and anaerobic bacteria. The bactericidal concentrations are generally within 1 doubling dilution of the minimum inhibitory concentrations (MICs).
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 against gram-positive and gram-negative organisms.
Mechanisms of Resistance: Bacterial resistance to meropenem may result from ≥1 factors: Decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins), reduced affinity of the target PBPs, increased expression of efflux pump component and production of β-lactamases that can hydrolyse carbapenems.
Localised clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.
The susceptibility to Meronem 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 Meronem includes the following species, based on clinical experience and the 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 methicillin resistant Staphylococcus aureus (MRSA) are resistant to meropenem], Staphylococcus spp. including Staphylococcus epidermidis [methicillin-susceptible strains only: Methicillin-resistant staphylococci including methicillin resistant Staphylococcus epidermis (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.
Gram Positive Anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus spp (including P. micros, P anaerobius, P. magnus).
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 (E. faecium can naturally display intermediate susceptibility even without acquired resistance mechanisms.
Species for Which Acquired Resistance May Be a Problem: Gram Negative Aerobes: Acinetobacter spp, Burkholderia cepacia, Pseudomonas aeruginosa.
Inherently Resistant Organisms: Gram Negative Aerobes: Stenotrophomonas maltophilia, Legionella spp.
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 eg, aminoglycosides or quinolones is common.
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.
Stenotrophomonas maltophilia, Enterococcus faecium and methicillin-resistant staphylococci have been found to be resistant to meropenem.
Pharmacokinetics: In healthy subjects the mean plasma half-life is approximately 1 hr; 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, 1,000 and 2,000 mg doses infused over 30 mins give mean Cmax values of approximately 23, 49 and 115 mcg/mL respectively, corresponding AUC values were 39.3, 62.3 and 153 mcg.h/mL. After infusion over 5 mins Cmax values are 52 and 112 mcg/mL after 500 and 1,000 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 1,000 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 27l.
Distribution: 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.
Metabolism: 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.
Elimination: Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50-75 %) of the dose is excreted unchanged within 12 hrs. 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 Insufficiency: Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance (CrCl). Dosage adjustments are necessary in subjects with renal impairment.
Hepatic Insufficiency: A study in patients with alcoholic cirrhosis has shown no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.
Children: Studies in children have shown that the pharmacokinetics of Meronem IV in children is similar to those in adults. The elimination half-life for meropenem was approximately 1.5-2.3 hrs in children <2 years and the pharmacokinetics is linear over the dose range of 10-40 mg/kg.
Elderly: Pharmacokinetic studies in the elderly subjects (65-80 years) have shown a reduction in plasma clearance which correlated with age-associated reduction in CrCl and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients with normal renal function or CrCl >50 mL/min (see Dosage & Administration).
Toxicology: Preclinical 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).
Meropenem is generally well tolerated by the central nervous system (CNS). Effects were seen only at very high doses of ≥2,000 mg/kg.
The IV LD50 of meropenem in rodents is >2,000 mg/kg. In repeat dose studies (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 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 rats was 120 mg/kg].
There was an increased incidence 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 IV formulation was well tolerated in animal studies.
The sole metabolite of meropenem had a similar profile toxicity in animal studies.
