Meropenem Monograph

Introduction

Meropenem represents a broad‑spectrum carbapenem antibiotic that has become a cornerstone in the treatment of severe, multidrug‑resistant bacterial infections. Its utility is derived from a combination of potent bactericidal activity, a favorable pharmacokinetic profile, and a relatively low propensity for inducing resistance when used appropriately. The monograph presented herein provides a systematic exploration of meropenem’s pharmacological attributes, clinical indications, and practical considerations for health‑care professionals. The following learning objectives are anticipated to be achieved through detailed engagement with this material:

• Identify the structural and mechanistic characteristics that distinguish meropenem from other β‑lactam antibiotics.
• Explain the pharmacokinetic principles governing meropenem distribution, metabolism, and elimination, including the impact of patient‑specific variables.
• Describe the pharmacodynamic parameters that correlate with clinical efficacy, particularly time above the minimum inhibitory concentration (T_MIC) and area under the concentration–time curve (AUC).
• Apply dosing strategies for meropenem in diverse clinical scenarios, incorporating renal function assessment and infusion schedules.
• Recognize common adverse effects, drug‑drug interactions, and resistance mechanisms associated with meropenem use.

Fundamental Principles

Core Concepts

Meropenem is a synthetic β‑lactam antibiotic belonging to the carbapenem class. Its core structure consists of a bicyclic β‑lactam ring fused to a dihydrothiazine ring, which confers resistance to many β‑lactamases. The drug’s mechanism of action involves irreversible inhibition of penicillin‑binding proteins (PBPs), thereby disrupting bacterial cell wall synthesis and leading to lysis.

Theoretical Foundations

The antibacterial activity of meropenem is governed by time‑dependent pharmacodynamics. Unlike concentration‑dependent agents, efficacy is maximized when the drug concentration remains above the pathogen’s MIC for a substantial portion of the dosing interval. Consequently, dosing regimens are tailored to maintain C_min > MIC for at least 40–50 % of the dosing interval, and often 60–70 % for critically ill patients. This principle is formalized in the parameter time above MIC (T_MIC).

Key Terminology

• MIC (Minimum Inhibitory Concentration) – the lowest concentration of an antibiotic that prevents visible growth of a microorganism in vitro.
• PK/PD (Pharmacokinetics/Pharmacodynamics) – the study of drug disposition and the relationship between drug concentration and effect.
• AUC (Area Under the Curve) – the integral of the concentration–time curve, representing total drug exposure.
• Cl (Clearance) – the volume of plasma from which the drug is completely removed per unit time.
• t_1/2 (Elimination Half‑Life) – the time required for the plasma concentration to decrease by 50 %.
• Renal Clearance – the clearance of a drug via glomerular filtration and tubular secretion.
• Influx/Outflux – movement of the drug across cellular membranes, influenced by passive diffusion and active transport.

Detailed Explanation

Mechanism of Action

Meropenem’s bactericidal effect is mediated through irreversible binding to PBPs located in the bacterial cell membrane. This interaction inhibits transpeptidation, a key step in peptidoglycan cross‑linking, ultimately compromising cell wall integrity. The drug demonstrates high affinity for a broad range of PBPs across Gram‑positive and Gram‑negative species, including Enterobacteriaceae, Pseudomonas aeruginosa, and anaerobes. The efficacy of meropenem is further enhanced by its stability against most β‑lactamases, including extended‑spectrum β‑lactamases (ESBLs) and carbapenemases, although some KPC and NDM enzymes can hydrolyze it.

Pharmacokinetic Profile

Meropenem is administered intravenously, as oral absorption is negligible. The drug exhibits rapid distribution, achieving a volume of distribution (V_d) close to the total body water. Peak plasma concentrations (C_max) are typically reached within 30–60 minutes following infusion. The elimination half‑life (t_1/2) ranges from 1 hour in patients with normal renal function to 4–6 hours in those with severe renal impairment. Renal excretion accounts for approximately 90 % of drug clearance, primarily via glomerular filtration, with a minor contribution from active tubular secretion. Hepatic metabolism is negligible; therefore, hepatic dysfunction has limited effect on meropenem disposition.

Mathematical Relationships

The concentration–time profile of meropenem can be described by the mono‑exponential decay model:

C(t) = C₀ × e^-k_elt

where C₀ is the initial concentration immediately post‑infusion, k_el is the elimination rate constant, and t is time. The elimination rate constant relates to the half‑life by:

k_el = ln(2)/t_1/2

Furthermore, the area under the concentration–time curve (AUC) can be approximated by the dose divided by clearance:

AUC = Dose ÷ Clearance

These relationships facilitate the calculation of dosing adjustments based on renal function. For example, in a patient with a creatinine clearance (CrCl) of 30 mL/min, the clearance of meropenem would be reduced to approximately 30 % of the normal value, necessitating dose reduction or extended dosing intervals.

Factors Influencing Pharmacokinetics

• Renal Function – as clearance is predominantly renal, impairment necessitates dose adjustment to avoid accumulation.
• Age – elderly patients tend to have reduced glomerular filtration, potentially prolonging t_1/2.
• Body Weight – high body mass can increase V_d, requiring higher loading doses.
• Albumin Levels – meropenem is minimally protein‑bound; hypoalbuminemia has limited impact on free drug concentrations.
• Concomitant Medications – drugs that compete for renal excretion (e.g., probenecid) may affect meropenem clearance.
• Disease State – critical illness can alter capillary permeability and organ perfusion, affecting distribution.

Clinical Significance

Relevance to Drug Therapy

Meropenem’s broad spectrum, coupled with its capacity to circumvent common β‑lactam resistance mechanisms, makes it an essential agent in the treatment of severe infections, particularly those caused by multidrug‑resistant organisms. Its pharmacokinetic characteristics allow for flexible dosing strategies, including continuous or extended infusions, which can be advantageous in achieving optimal T_MIC targets.

Practical Applications

Standard dosing regimens for patients with normal renal function typically involve 500 mg every 8 hours or 1 g every 8 hours, administered over 30‑60 minutes. In patients with renal insufficiency, dose or interval adjustments are guided by creatinine clearance values. For example, a patient with CrCl 20–49 mL/min may receive 500 mg every 12 hours, while those with CrCl < 20 mL/min may require 250 mg every 12 hours.

Clinical Examples

Consider a 68‑year‑old male with community‑acquired pneumonia caused by a ESBL‑producing Klebsiella pneumoniae. Meropenem at 1 g every 8 hours, infused over 30 minutes, would likely achieve effective concentrations above the MIC for the pathogen, given the high potency of the drug against Enterobacteriaceae. Adjustments would be made if the patient developed acute kidney injury, with dose reduction to 500 mg every 12 hours to prevent drug accumulation.

Clinical Applications/Examples

Case Scenario 1: Severe Sepsis due to Carbapenem‑Resistant Acinetobacter baumannii

In a 45‑year‑old ICU patient presenting with septic shock, cultures reveal Acinetobacter baumannii with a carbapenem MIC of 4 mg/L. Continuous infusion of 2 g per 24 hours may be employed to maintain plasma concentrations above the MIC for the entire dosing interval, thereby maximizing bactericidal activity. Renal function assessment is essential; if CrCl is 60 mL/min, the infusion rate remains unchanged, whereas a CrCl of 30 mL/min would prompt a reduction to 1 g per 24 hours.

Case Scenario 2: Hospital‑Acquired Pneumonia with Pseudomonas aeruginosa

A 70‑year‑old female with ventilated pneumonia shows Pseudomonas aeruginosa with an MIC of 1 mg/L. Standard intermittent dosing of 1 g every 8 hours administered over 30 minutes is adequate, but extended infusion over 4 hours could be considered to enhance T_MIC in patients with altered pharmacokinetics due to critical illness.

Problem‑Solving Approach

1. Identify the pathogen and its MIC from culture data.
2. Assess patient renal function using CrCl or estimated GFR.
3. Choose an appropriate dosing strategy (intermittent vs. continuous/extended infusion) based on the pathogen’s MIC, patient’s clinical status, and infusion logistics.
4. Adjust dose or interval according to renal function to avoid toxicity.
5. Monitor for adverse effects, particularly neurotoxicity in patients with reduced clearance.

Summary/Key Points

• Meropenem is a carbapenem antibiotic with a broad bactericidal spectrum, stable against most β‑lactamases.
• Time‑dependent pharmacodynamics govern efficacy; maintaining drug concentrations above the MIC for a significant portion of the dosing interval is critical.
• The drug is predominantly renally excreted; renal function dictates dosing adjustments to prevent accumulation.
• Standard dosing regimens vary with renal clearance: 1 g q8h for normal function, with reductions for impaired function.
• Continuous or extended infusion techniques can maximize T_MIC and are particularly useful in severe infections or patients with altered pharmacokinetics.
• Adverse effects are generally mild but may include seizures, particularly in patients with renal impairment or those receiving high doses.
• Resistance to meropenem typically arises through carbapenemase production; susceptibility testing remains essential for guiding therapy.

By integrating pharmacokinetic principles, clinical considerations, and evidence‑based dosing strategies, healthcare professionals can optimize meropenem therapy, thereby improving patient outcomes while mitigating the risk of resistance development.

References

1. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.