Optimisation of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa

Tam VH, Schilling AN, Neshat S, et al. Antimicrob Agents Chemother 2005:49;4920–4927.

Summary:

Antibiotics can be divided into two groups according to their in vitro bacterial kill characteristics – time dependent or concentration dependent. β-Lactams display a characteristic slow continuous (time-dependent) bactericidal activity. This contrasts with the bactericidal activity characteristic of aminoglycosides, which is concentration dependent. Although some experts have argued the case for maintaining serum levels of β-lactams above the minimum inhibitory concentration (MIC) for only 60% of the dosing interval, experimental studies have demonstrated that maximum killing of bacteria by β-lactam antibiotics occurs at concentrations 4–6 times the MIC.

Meropenem possesses a β-lactam ring and therefore should behave similarly, although the carbapenems may exhibit a post-antibiotic effect (PAE), a characteristic not shared by other β-lactams. The slow continuous kill implies there will be a benefit with longer (or continuous) infusion times, whereas the PAE suggests concentrations of drug can fall to low levels without regrowth of bacteria immediately.

Gram-negative bacterial resistance is an increasing problem worldwide, compounded by the limited number of new agents in development active against these bacteria. The situation therefore demands that we optimise the use of those agents we currently have available. Suboptimal dosing facilitates the emergence of resistance. The objective of this study was to determine the in vitro optimal bactericidal activity of meropenem and its propensity to suppress spontaneous emergence of resistance in Pseudomonas aeruginosa.

The study is a very impressive one, which examines the issue in detail using a complicated protocol. Two different Pseudomonal strains (wild type and AmpC derepressed mutant) were subjected to various meropenem concentrations with different rates of drug clearance from the area of the inoculum. These experiments were continued for an extended period (5 days), simulating a typical clinical scenario. Tobramycin was added to some samples to examine synergy. Initially, selective regrowth occurred if the minimum concentration (C_min): MIC ratio was less than approximately 2. Subpopulation regrowth was reduced when the C_min:MIC ratio was greater than 6 and when tobramycin was added.

These data therefore suggest that an extended meropenem infusion in combination with aminoglycoside will decrease the emergence of resistant Pseudomonas strains and support the concept of keeping high trough levels of a β-lactam antibiotic (ie at levels 4–6 times the MIC).

Whilst these are very important data with a ‘bottom-line message’ of the danger of underdosing, this experiment is a far cry from the clinical scenario, especially as in vitro data obviously cannot simulate innate immunity or the effect of neutrophils. There are ongoing clinical trials addressing continuous infusions of meropenem including some with extended infusions.

Clinically we need outcome data to validate this in vitro study. From a research point of view, we should be looking more closely at trough meropenem levels.

AIM core principles supported:

Antibiotic choice

• Administer antibiotics at the right dose for the appropriate duration

Learning points:

• Bacteria have a phenomenal ability to develop resistance to antibiotics
• It therefore requires us to use antibiotics appropriately and judiciously in an effort not to abuse these important drugs
• Underdosing of antibiotics can allow resistant, mutant strains of bacteria to grow and become a major management issue.