Why
is imipenem and meropenem resistance important?
Imipenem and meropenem are carbapenem antimicrobial agents used
to treat a variety of serious infections when an organism is resistant to the primary
agent of choice. Carbapenems also are used to treat nosocomial and mixed bacterial
infections. Resistance to these antimicrobial agents limits therapeutic options.
How much resistance to imipenem or meropenem occurs in clinical isolates?
In general, resistance to these carbapenems is rare. Within a
health care setting, increases in species-specific carbapenem resistance should be
monitored and sudden increases investigated to rule out an outbreak of resistant organisms
or spurious test results.
What gram-negative organisms are resistant to imipenem and/or meropenem?
Published reports indicate some resistance in a variety of
clinical gram-negative organisms, including Pseudomonas aeruginosa, Burkholderia
cepacia, Acinetobacter species, Proteus species, Serratia
marcescens, Enterobacter species, and Klebsiella pneumoniae. Stenotrophomonas
maltophilia isolates are intrinsically resistant to imipenem.
What causes resistance to carbapenems?
Resistance to carbapenems occurs either through bacterial
production of -lactamase
enzymes that hydrolyze (break down) the antimicrobial agent or through porin changes in
the bacterial cell wall that reduce the permeability of the drug into the organism. In
some organisms, both mechanisms may be present. DNA coding for enzyme production can be
passed from organism to organism via plasmids or can occur through mutation of an existing
-lactamase enzyme. Porin
changes arise through mutation.
What causes different levels of resistance?
The level of resistance is determined by the efficiency of the
enzyme for hydrolyzing the drug and by the number of resistance mechanisms present in the
organism. Organisms can produce more than one hydrolyzing enzyme and may show
modifications in more than one porin, producing high-level resistance to the carbapenems
(minimum inhibitory concentration [MIC] >16 g/ml). Organisms with decreased susceptibility produced by
porin changes alone often have lower MICs (2-8 g/ml).
Are some bacterial species more likely to produce testing errors with
carbapenems than other species?
Organisms with MICs near interpretation breakpoints have greater
potential for reporting errors. For example, isolates of Pseudomonas aeruginosa
often have MICs that are at or near the carbapenem intermediate (8 g/ml) and resistant (>16
g/ml) breakpoints (3).
Some species, such as Proteus mirabilis, P. vulgaris, and Morganella
morganiii, often have MICs (1-4 g/ml) just below the carbapenem intermediate breakpoint of 8 mg/ml. Most
other species of Enterobacteriaceae are very susceptible (<0.5 g/ml).
Can all susceptibility test methods accurately detect carbapenem resistance?
Broth microdilution methods usually detect carbapenem resistance
when the tests are performed properly. However, studies have shown false resistance to
imipenem in commercially prepared test panels due to degradation of the drug or to a
manufacturing problem where concentrations of imipenem were too low (1,2,4,5). When
performed properly, disk diffusion and agar gradient diffusion also are acceptable methods
for carbapenem testing.
What steps should laboratory personnel take to ensure accurate testing of
carbapenems?
Imipenem degrades easily. Studies suggest meropenem may be more
stable than imipenem. However, for either antimicrobial agent, storage conditions of
susceptibility panels, cards, and disks must be monitored carefully and quality control
results checked frequently. If possible, store supplies containing carbapenems at the
coldest temperature range stated in the manufacturer's directions. An additional test
method, such as agar gradient diffusion (i.e., Etest), can be used to verify intermediate
or resistant results.
Can the susceptibility test results of one carbapenem be used to predict
results for the other?
Meropenem is slightly more active than imipenem against
gram-negative organisms. However, the activity is species dependent. Meropenem is a
relatively new drug and more studies need to be published before susceptibilities of one
carbapenem can be used to predict the other.
(1) Carmeli, Y., K. Eichelberger, D. Soja, J. Dakos, L. Venkataraman, P.
DeGirolami, and M. Samore. 1998. Failure of quality control measures to prevent reporting
of false resistance to imipenem, resulting in a pseudo-outbreak of imipenem-resistant Pseudomonas
aeruginosa. Journal of Clinical Microbiology 36:595-597.
(2) Grist, R. 1992. External factors affecting imipenem performance in dried
microdilution MIC plates. Journal of Clinical Microbiology 30:535-536.
(3) National Committee for Clinical Laboratory Standards. 1999. Performance
standards for antimicrobial susceptibility testing. NCCLS approved standard M100-S9.
National Committee for Clinical Laboratory Standards, Wayne, PA.
(4) O'Rourke, E.J., K.G. Lambert, K.C. Parsonnet, A.B. Macone, and D.A.
Goldmann. 1991. False resistance to imipenem with a microdilution susceptibility testing
system. Journal of Clinical Microbiology 29:827-829.
(5) White, R.L., M.B. Kays, L.V. Friedrich, E.W. Brown, and J.R. Koonce. 1991.
Pseudoresistance of Pseudomonas aeruginosa resulting from degradation of imipenem
in an automated susceptibility testing system with predried panels. Journal of
Clinical Microbiology 29:398-400. |