The recent world-wide increase in carbapenem-resistant organisms (CPOs) has made it even more important to use these “last line” antibiotics with extreme care. They are the most broad-spectrum agents known and are often life-saving therapies for infections with organisms resistant to penicillins, cephalosporins and fluoroquinolones.
Imipenem, meropenem and ertapenem are the three currently available carbapenems in Canada.
Imipenem and meropenem have similar pharmacokinetics, pharmacodynamics and spectra of activity and are almost interchangeable when used empirically. Both imipenem and meropenem achieve therapeutic concentrations in the CNS, however, the penetration of meropenem into the CSF is higher. In addition, early studies have linked high-dose imipenem to seizures. Although epileptogenic potential of moderate-dose, renally-adjusted imipemen is no higher than that of meropenem, meropenem is still considered the carbapenem of choice for CNS infections. It has a label indication for the therapy of meningitis in children.
However CNS infections are rare indications and most hospitals in Canada have used imipenem as the predominant carbapenem with meropenem reserved for unusual cases of organisms (particularly Pseudomonas aeruginosa but also many Proteus spp., Providentia spp. and Morganella spp.) that may be meropenem susceptible and imipenem resistant, or for CNS infections (mostly brain abscesses) in which organisms resistant to other therapies have been recovered in culture.
Island Health has a policy of restriction of meropenem to Infectious Diseases or Medical Microbiologist specialists using a pre-approval mechanism. It is also available to physicians for the treatment of cystic fibrosis patients.
Ertapenem has a much longer half-life that facilitates once daily dosing. Its use has mostly been restricted to outpatient settings in Canada.
Organisms that carbapenems are not active against
- Methicillin (cloxacillin) resistant Staphylococcus aureus – MRSA
- Ampicillin resistant Enterococci
- Vancomycin resistant Enterococci – VRE
- Carbapenemase Producing organisms – CPO
Ertapenem is not active against Pseudomonas aeruginosa or Acinetobacter baumanii or Enterococci. There are strains of Pseudomonas aeruginosa, Proteus, Providentia and Morganella that are resistant to imipenem, meropenem or both. Most of these strains are resistant by means of a different mechanism than carbapenemase production.
If we can limit the majority of the use of carbapenems to those infections caused by microbiologically proven resistant organisms we will have succeeded.
ESBL E. coli, Klebsiella spp. and other enterobacteriaciae
E. coli is, by far, the most common bacteria recovered from blood cultures and the overwhelmingly most common cause of urinary tract infections. Klebsiella spp. are the second most common organsims causing urinary tract infections. Increasingly we are seeing strains that are capable of producing Extended-spectrum Beta-lactamases (ESBLs) though the prevalence in Island Health is not high. These organisms are often resistant to fluoroquinolones, Trimethoprim/sulfamethoxazole and aminoglycosides as well.
Carbapenems are recognized as very effective therapy for ESBLs and many authorities consider them superior to all other therapies for serious infections. This is controversial and there is growing evidence that piperacillin-tazobactam (when tested susceptible) is effective therapy even for serious infections. There is considerable interest in utilizing piperacillin-tazobactam as a “carbapenem sparing” strategy for ESBL infections.
“SPICE” organisms and “AmpC-producing E. coli“
Many members of the genera Serratia, Proteus, Citrobacter, Enterobacter and Morganella are inherantly resistant to all penicillin and cephalosporin antibiotics by means of the ability to produce AmpC beta-lactamases. These are the organisms commonly referred to as the “SPICE” group. In recent times strains of E. coli have acquired the ability to produce large amounts of AmpC beta-lactamases as well. All “SPICE” or “AmpC” organisms are resistant to all penicillins and cephalosporins including piperacillin/tazobactam and amoxicillin/clavlunate.
Organisms from the SPICE group show variable susceptibility to tetracyclines, fluoroquinolones, aminoglycosides and trimethoprim/sulfamethoxazole. If susceptibility is demonstrated, these agents are often a good alternative therapies to carbapenems, especially in UTIs.
If you want to read more about AmpC beta-lactamases, this is a good recent treatment of the subject. Clin. Micro. Rev – Beta Lactamases. But be warned, beta-lactamases are VERY complicated!
Empiric therapy of serious infections failing other therapies
The most common example is serious intra-abdominal infections for which source control is difficult or impossible. This is a circumstance that is very difficult to make judgements concerning clinical appropriateness of therapy. Generally, this would be a situation where consultation with the antimicrobial stewardship pharmacist, the stewardship physician, or even an ID consult is likely warranted.
Empiric therapy of recurrent infection is a patient known to be colonized or previously infected with resistant organism.
The most common example of this is serious UTI in a patient that has had prior infections. It is completely appropriate to initiate therapy with a carbapenem in this case with a careful eye to changing therapy if cultures do not prove recurrent resistant organism infection.
Opportunities for suggesting alternative therapies
Carbapenem was initiated empirically and specific culture results provides alternatives
This is probably the single most important means of optimizing the population use of carbapenems.
Carbapenem was initiated empirically but the “light of day” reveals less seriousness of clinical condition
While carbapenems are not “first-line” recommended empirical therapy for many conditions, they will be initiated especially by less experienced clinicians working in after-hours situations. However, often the circumstances surrounding the diagnosis and the decision to initiate therapy are much clearer the following day. There may have been an alternate non-infectious diagnosis established. There may have been an infectious diagnosis established for which a carbapenem is clearly not indicated.
If there has been clinical improvement on empirical antibiotic therapy, many clinicians are reluctant to change therapy. This is a more difficult scenario to be categorical about but it is certainly an area where well placed observations and suggestions are helpful. Generally, this would be a situation where consultation with the stewardship physician or even an ID consult may be warranted.
Redundant therapies are ordered
As carbapenems are so broadly active, they are most commonly appropriately used as mono-therapy. There are exceptions but some of the common additional antibiotics can be safely stopped while on a carbapenem.
Metronidazole or clindamycin are sometimes added for more “anti-anaerobic” activity. This is not warranted and to be dissuaded.
The addition of vancomycin may be appropriate especially if MRSA has been established as an infecting organism. However, it is often added as empirical “anti-enterococcal” therapy in complicated intra-abdominal infections and this is generally not advisable. Carbapenems are active against ampicillin susceptible enterococci exactly like piperacillin/tazobactam.