Meropenem microbiology

Meropenem
MERREM® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdosage
Clinical Studies
Dosage and Administration
Compatibility, Reconstitution, and Stability
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

Microbiology

Mechanism of Action

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.

Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).

In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Mechanism of Resistance

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibiotic-destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.

Cross-Resistance

Cross-resistance is sometimes observed with isolates resistant to other carbapenems.

Interactions with Other Antibiotics

In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Spectrum of Activity

Meropenem has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive bacteria

• Enterococcus faecalis (excluding vancomycin-resistant isolates)
• Staphylococcus aureus (β-lactamase and non-β-lactamase producing, methicillin-susceptible isolates only)
• Streptococcus agalactiae
• Streptococcus pneumoniae (penicillin-susceptible isolates only)
• Streptococcus pyogenes
• Viridans group streptococci

Gram-negative bacteria

• Escherichia coli
• Haemophilus influenzae (β-lactamase and non-β-lactamase producing)
• Klebsiella pneumoniae
• Neisseria meningitidis
• Pseudomonas aeruginosa
• Proteus mirabilis

Anaerobic bacteria

• Bacteroides fragilis
• Bacteroides thetaiotaomicron
• Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for meropenem. However, the safety and effectiveness of meropenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Gram-positive bacteria

• Staphylococcus epidermidis (β-lactamase and non-β-lactamase-producing, methicillin-susceptible isolates only).

Gram-negative bacteria

• Aeromonas hydrophila
• Campylobacter jejuni
• Citrobacter koseri (formerly diversus)
• Citrobacter freundii
• Enterobacter cloacae
• Hafnia alvei
• Klebsiella oxytoca
• Moraxella catarrhalis
• Morganella morganii
• Pasteurella multocida
• Proteus vulgaris
• Serratia marcescens

Anaerobic bacteria

• Bacteroides distasonis
• Bacteroides ovatus
• Bacteroides uniformis
• Bacteroides ureolyticus
• Bacteroides vulgatus
• Clostridium difficile
• Clostridium perfringens
• Eubacterium lentum
• Fusobacterium species
• Prevotella bivia
• Prevotella intermedia
• Prevotella melaninogenica
• Porphyromonas asaccharolytica
• Propionibacterium acnes

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of meropenem powder. The MIC values should be interpreted according to the criteria provided in Table below.

Diffusion techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2,3 and requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-mcg of meropenem to test the susceptibility of microorganisms to meropenem. The disk diffusion interpretive criteria are provided in Table below.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to meropenem as MICs can be determined by a standardized test method.4 The MIC values obtained should be interpreted according to the criteria provided in Table below.

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the ntimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard meropenem powder should provide the following range of values noted in Table below.

References

Adapted from the FDA Package Insert.