The growing concern for multi-drug resistant organisms has been addressed in previous Pharmacology Consult columns. A review of the newest carbapenem, doripenem, was discussed in July 2008.
Some practitioners believe that a carbapenem is a carbapenem is a carbapenem. Four carbapenems exist in the U.S. market but are they all the same? From a clinical standpoint and pharmacologic standpoint, each drug has its own niche, making choosing a particular carbapenem tricky in clinical practice.
Imipenem/cilastatin (Primaxin, Merck), meropenem (Merrem, AstraZeneca), ertapenem (Invanz, Merck) and doripenem (Doribax, Ortho-McNeil) are the four beta lactam antibiotics of the carbapenem class. Imipenem/cilastatin was approved first in 1987, followed by meropenem in 1996, ertapenem in 2001 and then, most recently, doripenem in 2007. These agents are known for the extremely broad spectrum of activity, including gram positive, gram negative and anaerobic coverage.
Carbapenems have been used clinically to treat many infections. In clinical practice, these are the go-to agents when multi-drug resistant organisms are a concern or an infection is considered polymicrobial. But what sets each agent apart: the pharmacokinetic (PK)/pharmacodynamic PD) properties, their spectrums of coverage, indications, mechanisms of resistance or adverse effects?
Mechanism of action
Carbapenems exhibit bacteriocidal activity by binding to the penicillin-binding proteins (PBP), thus preventing linking of the peptidoglycan strands and further synthesis of the bacterial cell wall. Imipenem/cilastatin is susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) and therefore requires co-administration with a DHP-1 inhibitor cilastatin. The later carbapenems have increased stability to DHP-1 and do not require a DHP-1 inhibitor. Meropenem and doripenem are thought to be the more potent in vitro agents against gram negative organisms. Meropenem has a niche in its spectrum of coverage. It has coverage of Burkholderia cepacia. This increased in vitro activity is due to the binding capabilities of each agent.
In general, the carbapenems have the most bacteriocidal activity when binding with PBPs 1a, 1b and 2. Meropenem and ertapenem for instance, have the highest affinity to PBP2, followed by PBP 1a and 1b. But these two agents uniquely have affinity for PBP3. PBP3 is species specific for Pseudomonas aeruginosa. The third-generation cephalosporins act on PBP3. Doripenem has shown strong affinity for PBP3 as well as PBP 2 (found on S. aureus) and PBP 4 (found on E. coli). Imipenem/cilastatin preferentially binds to PBP2, followed by 1a and 1b, and has the weakest affinity for PBP3. The niche in the mechanisms of action is observed in vitro but the true impact in vivo is difficult to interpret.
Mechanism of resistance
The stability of the carbapenems against gram-negative pathogens, which are resistant to other beta-lactams, comes from the protection against AmpC beta-lactamases and the extended-spectrum beta-lactamases (ESBLs). These enzymes can be produced by a variety of gram negative organisms (ie E. coli, Klebsiella pneumoniae, Enterobacter spp. and Serratia marcescens). Jones RN and Fritsche TR et al. have studied the in vitro activity of imipenem, meropenem and doripenem against ESBLs.
When comparing wild-type and ESBL producing strains of E coli or Klebsiella, they found no increase or a one dilution doubling in MIC90. Ertapenem MIC90 increased by two to three doubling dilutions for ESBL producing isolates and a four doubling-dilutions for AmpC beta-lactamase isolates. By the Clinical and Laboratory Standards Institute (CLSI) breakpoints, ertapenem still maintained susceptibility to these organisms. Ge Y et al. conducted a similar study observing AmpC beta-lactamase producing strains of Enterobacter spp. and Serratia marcescens. Similar results were found for imipenem/cilastatin, meropenem and doripenem as the previous study. This in vitro data suggest that ertapenem is less stable than the other carbapenems to the beta-lactamase enzymes and may confer resistance more rapidly in vivo.
P. aeruginosa has become resistant to many of the beta-lactam antibiotics. It remains fairly sensitive to the carbapenems, excluding ertapenem. Ertapenem lacks pseudomonal activity and is a niche of this agent. P. aeruginosa is associated with increasing MICs of the imipenem, meropenem and doripenem but needs an AmpC beta-lactamase to become resistant. The mechanisms for the increase of MICs is associated with loss of the porin Opr D, combined with activity of chromosomal beta lactamase (Amp C); in addition, overexpression of multi-drug efflux pumps is considered to confer meropenem and doripenem resistance. Meropenem and doripenem are thought to maintain more antipseudomonal activity than imipenem/cilastatin because of the multiple mechanisms of resistance required to cause resistance to P. aeruginosa. Another consideration is the enzymes referred to as carbapenemases. These enzymes hydrolyse all penicillins and cephalosporins, but may also lead to rapid hydrolysis of carbapenems.
Although the carbapenems spectrum of activity is broad, some gram positive organisms exhibit intrinsic resistance. Methicillin-resistant S. aureus (MRSA) and Enterococcus faecium have intrinsic resistance to the carbapenems. All the carbapenems have poor binding affinity for PBP 2a (found on MRSA) and PBP 5 (found on E. faecium). Imipenem/cilastatin and doripenem have more potent activity against gram positive aerobic bacteria. Imipenem/cilastatin also demonstrates lower MICs for E. faecalis compared with the other carbapenems.
In clinical practice, it is relevant to consider the in vitro mechanisms of action and each agents mechanism of resistance. If treating a P. aeurginosa, which has demonstrated some resistance to other beta-lactam antibiotics, it is critical to monitor isolates for MIC creeps and be aware that some isolates may mount resistance to the carbapenems. Pathogens such as Stenotrophomonas maltophilia and Aeromonas spp., may also produce carbapenem resistant strains (ie due to production of metallo-beta-lactamases production). When treating polymicrobial infections, it is essential to remember the intrinsic resistance to MRSA and E. faecium to the carbapenems and choose other first-line gram positive antibiotics for these organisms.
Each of the carbapenems are formulated as parenteral agents. Imipenem/cilastatin and meropenem are administered as either a 500 mg or 1 gm dose IV every six to eight hours and each achieve fairly similar Cmax (mg/L) and AUC (mg· h/L). Ertapenem is unique in the fact it is administered once daily as a 1 gm dose. Ertapenem achieves the highest Cmax (mg/L) of the carbapenems at 154.9 mg/L. Doripenem is approved for a dose of 500 mg IV every six to eight hours and achieves similar PK parameters as imipenem/cilastatin and meropenem.
The protein binding accounts for major PK differences between each drug. Ertapenem is extensively protein bound at 92% to 95%, followed by imipenem/cilastatin at 20%, doripenem 8.1% and meropenem 2% plasma protein bound (PPB).
Again this is a niche for ertapenem and makes it favorable for once daily dosing. Each of these agents are extensively eliminated renally. Dose adjustments are necessary in renal impairment.
The carbapenems have overall safe adverse effect profiles. The most commonly reported adverse effects include local irritation at injection site, diarrhea, rash, nausea, vomiting and pruritis.
Clinical controversy exists around the noted adverse effect of seizures in the class. In a post- marketing surveillance, the incidence of imipenem/cilastatin seizures was 1.5% to 2%. Patients who developed this adverse effect had impaired renal function, known CNS disease or infection, history of seizures or stroke, as well as administration of 1 gm IV every six hours. This adverse effect has since been re-evaluated and a complex dosing strategy has been included in the package insert for imipenem/cilastatin.
Clinicians must evaluate the patients type or severity of infection, and determine if the organism is fully or moderately susceptible to determine the patients total daily dose. The next step is to evaluate the patients body weight and creatinine clearance to determine the appropriate dose and frequency of administration. The renal adjustment for meropenem, ertapenem and doripenem are straight forward. The reported seizure incidence is listed as less than 1% for each carbapenem.
Are all carbapenems the same? Clearly, each agent has its own distinct features. The carbapenem class provides the most broad-spectrum coverage of all the anti-infectives marketed. The agents are bacteriocidal and have stability against various beta-lactamases, particularly the AmpC and EBSLs.
These extensive in vitro and in vivo characteristics lead to these agents being used as a go-to drug for moderately-to-severely ill patients or when a polymicrobial infection is suspected. Knowing the niche of each agent allows clinicians to choose the best agent to fit their patients needs. It is important for clinicians to understand the ability of the agents to treat infectious diseases, it is also critical to remember to conserve these agents. Minimal research is being conducted on gram negative agents; therefore, reserving this class for the known utility will be crucial to treat multi-drug resistant organisms currently and in the future.
For more information:
- Kimberly Boeser, PharmD, is the infectious disease clinical pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program.
- Jones RN, Sader HS, Fritsche TR. Comparative activity of doripenem and three other carbapenems tested against gram negative bacilli with various beta-lactamase resistant mechanisms. Diagn Microbiol Infect Dis. 2005;52:71-74.
- Ge Y, Wikler MA, Sahm DF, et al. In vitro antimicrobial activity of doripenem, a new carbapenem. Antimicrob Agents Chemother. 2004;48(4):1384-1396
- Zhanel GG, Wiebe R, Dilay L, et al. Comparative Review of the Carbapenems. Drugs. 2007;67(7):1027-1052.